Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(=O)Nc1cccc(O)c1
Product: CC(=O)Nc1cccc(OC(=O)N(C)c2ccccc2)c1

Procedure:
The title product was prepared from 3-acetamidophenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (66%, white solid). HPLC-MS: m/z=285.1 (M+1); Rt: 3.09 min.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][C:4]=2[CH:3]=[N:2]1.Br[C:19]1[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[C:13]([O:12][C:11]([NH:10][CH:6]1[CH2:7][CH2:8][C:9]2[N:1]([C:19]3[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=3)[N:2]=[CH:3][C:4]=2[CH2:5]1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCc2[nH]ncc2C1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1sc(-n2ncc3c2CCC(NC(=O)OC(C)(C)C)C3)nc1C
Yield: 22.7 %

Procedure:
The same operation as in Example (223a) was performed using tert-butyl 4,5,6,7-tetrahydroindazol-5-ylcarbamate obtained in Example (242b) (246 mg, 1.04 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (519 mg, 2.07 mmol), copper (I) iodide (40 mg, 0.21 mmol), proline (48 mg, 0.42 mmol) and potassium carbonate (431 mg, 3.12 mmol), to obtain 96 mg of ethyl 2-{5-[(tert-butoxycarbonyl)amino]-4,5,6,7-tetrahydro-1H-indazol-1-yl}-4-methyl-1,3-thiazole-5-carboxylate as a pale yellow solid (23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:33][CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CO>O1CCOCC1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:35]([CH2:34][Cl:33])=[CH:36][CH:37]=4)=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Yield: 74 %

Procedure:
To a solution of 0.35 g (0.97 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 20 ml dioxane were added 0.2 ml triethyl amine, 12 mg DMAP and 0.238 g (1.26 mMol) 4-chloromethyl-benzoyl chloride, dissolved in 1 ml of dioxane. The reaction mixture was heated to reflux for 3 h. Then 5 ml methanol were added. The solvent was evaporated to dryness, the residue taken up in ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:1) to yield 0.37, (74%) 4-[2-(4-chloromethyl-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white foam. ES-MS m/e (%): 514 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].C(Cl)(=O)OCC.[BH4-].[Na+].Cl>C1COCC1.C(N(CC)CC)C>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:6]=[CH:7][CH2:8][OH:9])[CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C=CCO)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxycinnamic acid (1.5 g) was dissolved in THF (100 mL), triethylamine (0.64 mL) was added to the solution under ice cooling, and ethyl chlorocarbonate (0.44 mL) was then added dropwise thereto. After stirring the resultant mixture at room temperature for 1 hour, sodium borohydride (477 mg) was added to the mixture under ice cooling. After stirring the resultant mixture at room temperature for 1 hour, diluted hydrochloric acid was added to the reaction mixture to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH:28]2[CH2:32][CH2:31][CH:30]=[CH:29]2)[CH:25]=[C:24]([CH3:33])[C:23]=1[OH:34].C1(C)C=CC=CC=1>CC(CC(C)=O)C.C1COCC1>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([CH:31]2[CH2:30][CH2:29][CH:28]([C:26]3[CH:25]=[C:24]([CH3:33])[C:23]([OH:34])=[C:22]([CH3:21])[CH:27]=3)[CH2:32]2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc(C2C=CCC2)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C2CCC(c3cc(C)c(O)c(C)c3)C2)cc(C)c1O

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 286 g of 2,6-dimethylphenol and 40 g of p-toluenesulfonic acid (hereinafter “PTS”) were introduced, and a solution of mixture of 106 g of 2,6-dimethyl-4-(2-cyclopenten-1-yl)phenol and 106 g of toluene was added dropwise over a period of 1 hour while stirring the mixture kept at 100° C., followed by further stirring for 4 hours at 80° C. To the reaction solution thus obtained, THF and MIBK were added, and the resultant solution was washed with water until it turned neutral, followed by removal of the solvent and 2,6-dimethylphenol using an evaporator.
Reaction SMILES: BrBr.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=3)=[N:20]2)=[S:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl.C(O)(=O)C>[NH2:24][C:23]1[N:19]([C:17]2[S:18][C:12]3[CH:11]=[C:10]([O:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:15]=[CH:14][C:13]=3[N:16]=2)[N:20]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:28][CH:27]=2)[N:22]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=S)Nc1ccc(Oc2ccccc2)cc1
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1-c1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %

Procedure:
Bromine (7 μl, 1 equivalent) was added to a stirred suspension of 5-amino-3-(4-sulfamoyl-phenylamino)-[1,2,4]triazole-1-carbothioic acid (4-phenoxy-phenyl)-amide in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 18 hours. A solution of bromine (7 μl) in acetic acid (1 ml) was then added to push the reaction to completion: the reaction mixture was stirred for a further four hours. A white solid precipitated and was removed by filtration to afford the title compound (5 mg; 7% yield). 1H NMR (400 MHz, DMSO-d6) 7.05-7.20 (8H, m), 7.35-7.50 (4H, m), 7.70-7.75 (2H, d), 7.80-7.85 (2H, d), 9.90-9.95 (1H, s); MS (ES+) m/e=480
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C2C(=CC=CC=2)CCC1>[CH2:11]([C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1)[CH3:12]
Reactant: CCC(=O)NCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccc2c(c1)CCCC2
Product: CCC1=NCCc2ccccc21
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A mixture of N-(2-phenylethyl)-propionamide (10 g, 56.4 mmol) and phosphorus pentoxide (80 g, 563 mmol) in tetralin (500 ml) was heated at reflux for 15 min, cooled, further phosphorus pentoxide (80 g) was added and reflux was resumed for 15 min. After standing overnight the tetralin was decanted, the residue was decomposed with ice-water, the suspension was filtered through celite and washed with two portions of ether. The aqueous solution was basified with concentrated ammonium hydroxide, extracted with three portions of ether, the extracts were dried (MgSO4) and the solvent was evaporated giving a red solid (5.0 g, 55.7%); MS [M+H]+ 160.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[NH2:12][C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[C:15](F)[N:14]=1>>[NH2:12][C:13]1[N:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: Nc1nc(F)ccc1C(=O)O
Agent: O=C1Nc2ccccc2C1=O
Product: Nc1ncccc1C(=O)O

Procedure:
Using the procedure in Example 56 and substituting 5-fluoroisatin for isatin and 2-amino-6-fluoropyridine-3-carboxylic acid (Rogers et al. U.S. Pat. No. 4,383,851, 1983) for 2-aminonicotinic acid gives the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].Cl[CH2:9][C:10]([NH:12][C:13]1[C:14]([I:28])=[C:15]([CH2:21][CH:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24])[C:16]([I:20])=[CH:17][C:18]=1[I:19])=[O:11]>>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:9][C:10]([NH:12][C:13]1[C:14]([I:28])=[C:15]([CH2:21][CH:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24])[C:16]([I:20])=[CH:17][C:18]=1[I:19])=[O:11]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCl)c1I)C(=O)O
Reactant: NCCNCCN
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CNCCNCCN)c1I)C(=O)O
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To 217 g of diethylenetriamine (product commercially available) (2.1 mol), under stirring and under nitrogen atmosphere, 259 g of compound (A) 3-[(2-chloroacetyl) amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.40 mol) are added. The mixture is kept at 50° C. for 3 h and, after cooling, is extracted with three 500-ml portions of CH2Cl2. After evaporation of the solvent, the residue is dissolved in 500 ml of H2O and acidified with 300 ml of 37% HCl. The resulting solution is counterflow extracted according to Craig with n-BuOH. A residue is obtained, which is purified as trihydrochloride by crystallisation in abs. EtOH after addition of 37% HCl. 187 g of 3-[[[2-[(2-aminoethyl)amino]ethyl]amino]acetylamino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.227 mol) are obtained.
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Br:20])[N:7]=[C:6]([C:21](=[S:23])[NH2:22])[C:5]=1[S:24]([CH3:26])=[O:25]>>[CH3:1][S:23][C:21]([C:6]1[C:5]([S:24]([CH3:26])=[O:25])=[C:4]([NH2:3])[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Br:20])[N:7]=1)=[NH:22]
Reactant: CI
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Product: CSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c(N)c1S(C)=O

Procedure:
In a manner similar to that described in EXAMPLE 2, methyl iodide was reacted with 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide (Compound 6, prepared as described in applicants' concurrently filed, copending application referenced in EXAMPLE 2 above) to give 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid methyl ester having a melting point of 203.5° C. compound is referred to hereinafter as Compound 4.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1>[C:1]1([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1ccccc1
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Reaction time: 10 h
Yield: 96 %

Procedure:
A 158 g (1.0 mole) quantity of benzenesulfonic acid, 94 g (1.2 moles) of benzene and 5 g of 12-tungstophosphoric acid (H3PW12O40.29H2O) were refluxed with heating and stirring. The reaction system was kept at the reflux temperature for 10 hours, while refluxing the benzene and removing the produced water by subjecting the azeotropic mixture with the benzene to phase separation. The reaction mixture was diluted with 150 g of benzene and the catalyst was separated by filtration. The mother liquor was washed with water and the benzene was distilled off under reduced pressure, giving 210 g of diphenylsulfone (96% yield, m.p. 124° to 128° C.).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:30]
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: COc1cccc(/C=C/C(=O)Nc2cnn(CCCCC(C)=O)c2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.85 min; [M+H]+=372.16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:5]#[N:6]
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A mixture of 3-bromo-4-fluorobenzonitrile (1.60 g, 8.00 mmol), 4-chlorophenol (1.028 g, 8 mmol) and potassium carbonate (2.487 g, 24 mmol) in DMSO (20 mL) was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction was diluted with aqueous ammonium chloride (50 mL) and extracted with EtOAc (3×30 mL). The combined organic extract was washed with water (2×30 mL) and dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[F:23][C:24]1[C:25]([OH:30])=[N:26][CH:27]=[CH:28][CH:29]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]4=[O:30])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1ncccc1F
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cccc(F)c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 12.4 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), 3-fluoro-2-hydroxypyridine (46 mg, 0.40 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube, was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 429.0 and 431.0 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[CH:7].I[C:10]1[C:18]([N+]([O-])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[C:7][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: C#CCNC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.3 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (11 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 25 mg, 23%).
Reaction SMILES: C[CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@@H:22](O)[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=[O:7])([CH3:5])[CH3:4].[NH4+].[CH4:33]>C1(C)C=CC=CC=1>[CH3:33][CH2:4][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:27][C:26](=[O:28])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=[O:7])([CH3:5])[CH3:2]
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Reactant: C
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The ammonium salt of step 3 (15 gm) is suspended in toluene (500 ml) and heated at 100° C. under a constant sweep of nitrogen for 5 hours. The solution is cooled to 25° C., activated charcoal (1 gm) is added stirred for 30 minutes and then filtered through celite-bed. The filtrate is concentrated under reduced pressure to a volume of 70 ml. Cyclohexane (200 ml) is added, refluxed for 20 minutes, cooled to 10° C. and stirred for 3 hours at 10° C. The precipitated solid is filtered and washed with cold cyclohexane (100 ml) and dried to obtain simvastatin as white crystalline product. The product is re-crystallized from absolute ethanol to obtain 13 gm of simvastatin (HPLC Purity 99.7%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=2)[N:8]=1)=[O:6])[CH:2]=[CH2:3].O.O.Cl[Sn]Cl>CO>[CH2:1]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc2cc([N+](=O)[O-])ccc2n1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CCOC(=O)c1ccc2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 2-allyloxycarbonyl-6-nitroquinoline (1.25 g; 4.8 mM) in MeOH (20 ml) was added SnCl2.2H2O (7.65 g, 33.6 mM). After stirring at ambient temperature for 3 hours, the mixture was evaporated to dryness and the residue partitioned between an aqueous solution of NH4OH (pH 8.5) and ethyl acetate. The organic phase was concentrated and purified by subjecting to flash chromatography, eluting with ethyl acetate/petroleum ether (65/35) to give 2-allyloxycarbonyl-6-aminoquinoline (280 mg; 28%).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH:28][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:24]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCS(=O)(=O)C2)s1
Yield: 82 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using 1,1-dioxidotetrahydrothien-3-ylamine instead of rac-2-amino-1-butanol, to the title compound (174 mg, 82%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:18]([I:19])=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]\N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>CCO>[NH2:23][C:22]1[N:24]=[CH:12][C:7]2[CH2:8][C:9](=[O:11])[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([I:19])=[CH:17][C:5]=3[C:6]=2[N:21]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C1/CC(=O)Nc2cc(Cl)c(I)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
A suspension of (4Z)-8-chloro-4-[(dimethylamino)methylene]-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (9.50 g, 24.3 mmol), guanidine hydrochloride (2.56 g, 26.8 mmol), and potassium carbonate (11.1 g, 80.3 mmol) in EtOH (143) was allowed to stir while heating at 70° C. in a sealed reaction vessel. After 19 h, the reaction mixture was allowed to cool to room temperature then added to water (200 mL) and allowed to stir for 1 h. The resulting tan solid was collected via suction filtration, washed with water, and dried in a vacuum oven to give 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (7.69 g, 82%). LCMS (FA): m/z=387 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:11][CH:10]=1.[CH2:31](I)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:30][C:20]1[CH:21]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:23]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH2:31][CH3:32])[N:19]=2)=[CH:11][CH:10]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3nn[nH]n3)cc2)c(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nnc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)n1

Procedure:
100 mg of 5-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2H-tetrazole, 48 mg of ethyl iodide and 141 mg of potassium carbonate are stirred for 4 hours at 50° C. in 3 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield 5-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-ethyl-2H-tetrazole (compound 1.4).
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@]1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
The compound (110 mg, 0.23 mmol) obtained in Example 3-3) was dissolved in methanol (3 mL). A 4 M solution (0.54 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (20 mL) and methanol (1 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (89 mg, 43%) in a white solid form.