Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:14][C:13]2[C:8]1=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)(=O)=O.[CH3:19][O:20][C:21]1[C:37]([O:38][CH3:39])=[CH:36][C:24]2[CH2:25][C:26](=[O:35])[N:27]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[CH:28]=[CH:29][C:23]=2[CH:22]=1>>[CH3:34][N:33]([CH2:6][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH2:14]1)[CH2:32][CH2:31][CH2:30][N:27]1[C:26](=[O:35])[CH2:25][C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[C:37]([O:38][CH3:39])[CH:36]=2)[CH2:29][CH2:28]1
Reactant: COc1cc2c(cc1OC)[C@@H](COS(C)(=O)=O)C2
Reactant: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 7, starting from (7S)-(iodomethyl)-3,4-dimethoxybicyclo-[4.2.0]octa-1,3,5-triene (or from (7S)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl methanesulphonate) and from 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3-dihydro-2H-3-benzazepin-2-one, there is obtained a compound which is hydrogenated by following the procedure described in patent specification EP 0 534 859 (Example 1, Step D) to yield ivabradine base, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>C(Cl)Cl>[C:27]1([CH2:26][NH:33][CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 20 h
Yield: 99.9 %

Procedure:
1,4-cyclohexanedione ethylene ketal (5.00 g, 32.0 mmol, 1 eq.), sodium triacetoxyborohydride (8.14 g, 38.4 mmol, 1.2 eq.) and benzylamine (3.50 mL, 32.0 mmol, 1 eq.) were mixed in methylene chloride (100 mL) at room temperature. Stirred for 20 hours. Added 50 mL of 1.0 N NaOH. Stirred for 10 minutes. Extracted 3 times with methylene chloride (50 mL). The organic layers were combined, dried over sodium sulfate and stripped to give N-(phenylmethyl)-1,4-Dioxaspiro[4.5]decan-8-amine (7.91 g) of a light amber oil as product. Yield=100%. LCMS detects (M+H)+=248.26.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](OC(ON=C(C#N)C(OCC)=O)=O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(OCC)(=O)C>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:14][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 53.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-proline (1.25 g) and triethylamine (0.70 ml) in ethyl acetate (15 ml), ethyl 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetate (1.55 g) in powder form is added at room temperature while stirring. The resulting mixture is stirred for 4 hours and then extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The residue is recrystallized from an ethanol-petroleum ether mixture to give N-benzyloxycarbonyl-L-proline p-nitrophenyl ester (1.0 g). M.P. 94° - 96°C.
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[CH:11][CH:10]=1>O.O1CCOCC1>[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:1])=[CH:13][CH:14]=1
Reactant: CCCCCCCCC(F)COc1ccc(C(C)=O)cc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCC(F)COc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 11.3 g of sodium hydroxide in 75 ml of water was charged in a 300 ml-three necked flask and cooled to 0° C., and 12.3 g of bromine was added thereto in 15 minutes under stirring, followed by addition of 30 ml of dioxane. The resultant mixture solution was added dropwise in 40 minutes to a solution which was obtained by dissolving 5.2 g of p-(2-fluorodecyloxy) acetophenone in 170 ml of dioxane followed by addition of 10 ml of water, and subjected to reaction for 3.5 hours while being kept below 10° C. Thereafter, the excessive hypobromite was removed by addition of a hydrosulfite aqueous solution, followed by acidification with addition of 6N-hydrochloric acid aqueous solution, and addition of 500 ml of water to precipitate a crystal, which was then recovered by filtration. The crystal was recrystallized from isopropyl ether to obtain 4.1 g of p-(2-fluorodecyloxy)benzoic acid.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:19]([O:21][C:22]1[C:31]([O:32][CH2:33][CH3:34])=[C:30]([O:35][CH2:36][CH3:37])[C:29]([N+:38]([O-:40])=[O:39])=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]1[CH:24]1[C:23]2[C:28](=[C:29]([N+:38]([O-:40])=[O:39])[C:30]([O:35][CH2:36][CH3:37])=[C:31]([O:32][CH2:33][CH3:34])[C:22]=2[O:21][CH2:19][CH3:20])[C:26](=[O:27])[O:25]1
Reactant: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Reactant: COc1cc2c(c(OC)c1OC)C=[N+](C)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2c(cc(OC)c(OC)c2OC)CCN1C

Procedure:
235 g (0.647 mole) of 2-methyl-6,7,8-trimethoxy-3,4-dihydro-isoquinolinium iodide (described in J. Chem. Soc. 1951, 1150), 201.4 g of 4,5,6-triethoxy-7-nitrophthalide and 107 g of potassium carbonate are added to 1.240 liters of methanol. After stirring for 24 hours at a temperature below the boiling point of the solvent, 730 ml of water is added and the reaction solution is allowed to crystallise. The crystals are collected by filtration, washed with water and dried, providing 270 g of C27H34O10N2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][C:35]([OH:39])([CH3:38])[CH2:36]O.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:34][C:35]([CH3:38])([OH:39])[CH3:36])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)O
Temperature: 10 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
N-Benzyloxycarbonyl-L-valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol), and), and dicyclohexylcarbodiimide (2.04 g, 9.9 mmol, in 20 mL CH2Cl2) were added to 2-methyl-1,2-propanediol (12.2 mmol) in 30 mL dry CH2Cl2, with cooling in an ice bath. DMF (5 mL) was added. After stirring for 5 h at 10° C., the reaction mixture was filtered, concentrated, and then redissolved in ethyl acetate. The organic solution was washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated. Flash column chromatography (silica, 2/1 petroleum ether—ethyl acetate) gave 2.3 g of the title compound.
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[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1.C(O)C>[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:33]([N:35]=[C:36]=[S:37])=[O:34].[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[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[O:34])=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(N=C=S)N1CCc2ccccc2C1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCc5ccccc5C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Commercially available 1,2,3,4-tetrahydroisoquinoline (50 mg) was dissolved in chloroform (10 ml), and triphosgene (111 mg) was added to the solution. The mixture was stirred at room temperature for 2 hr. The solvent was removed by distillation to give 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl chloride. 1,2,3,4-Tetrahydro-2-isoquinolinecarbonyl isothiocyanate was prepared using this compound as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 94%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and 4-bromophenyl acetohydroximoyl chloride (168 mg, 0.677 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 15 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (33 mg, 24%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2].[H-].[Na+].[CH:28](I)([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:28]([CH3:30])[CH3:29])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)c(C)cc2[nH]c1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(C)c(C)cc2c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% in oil) (270 mg), followed by stirring at room temperature for 30 minutes. To this solution was added isopropyl iodide (0.9 ml), followed by stirring at 70° C. for 5 hours. After the mixture was cooled, ethyl acetate was added, and this mixture was washed successively wfth dilute hydrochloric acid, aqueous potassium carbonate and Water and then dried, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1), to yield 4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic acid ethyl ester as colorless crystals (1.72 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(N3CCN(c4ccccc4)CC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH2:1][CH:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[OH:4][CH2:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15.7 ml (0.012 mol) of triethylamine in 100 ml of CH2Cl2, cooled to 0° C., was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2Cl2 and then washed with 60 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a solid. Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94° C. Anal. for C11H15NO6S: Calc'd: C, 45.7; H, 5.2; N, 4.8; S, 11.1; Found: C, 45.6; H, 5.2; N, 4.8; S, 11.1.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]([N+:1]([O-:3])=[O:2])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (E)-(2-nitrovinyl)benzene (110 g, 0.738 mol) and TFA (8.42 g, 0.073 mol) in DCM (500 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)-methanamine (351.4 g, 1.476 mol) in DCM (500 mL) drop-wise at 0° C. for a period of 30 min. Then the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the mixture was concentrated in vacuo, dissolved in water, and extracted into EtOAc (×2, 1.0 L). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash chromatography (20-80% petroleum ether/EtOAc) to afford (3S and R, 4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine. MS ESI calc'd. For C17H18N2O2 [M+1]+ 283. found 283.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17]>C(#N)C.C(OCC)C>[F:17][C:16]([F:19])([F:18])[C:8](=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:12][C:11]([OH:10])=[O:13]
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccccc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred solution of phenylmaleic anhydride (18.7 g, 0.107 mol) in acetonitrile (180 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (18.6 g, 0.127 mol), followed by the drop-wise addition of CF3SiMe3 (18.58 ml, 0.127 mol), under nitrogen. The reaction mixture was stirred for 1 h, and was then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The separated aqueous layer was acidified to pH=1 by the addition of conc. hydrochloric acid. This mixture was extracted with dichloromethane. The separated organic layer was dried (Na2SO4), and the solvent was evaporated in vacuo to yield D1 (22.6 g, 86%) as a mixture of isomers (80/11 ratio by LCMS). C11H7F3O3 requires 244; Found 243 (M-H−).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:23][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccc2ccc(COc3cccc(CBr)c3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To the benzylic alcohol of Step 2 (47.0 g, 157 mmol) and CBr4 (60.08 g, 181 mmol) in CH2Cl2 (750 mL) at 0° C., a solution of 1,2-bis(diphenylphosphino) ethane (DIPHOS, 36.29 g, 91.1 mmol) in CH2Cl2 (350 mL) was added and the resulting mixture was stirred at 0° C. for 45 min. and at r.t. for 30 min. Ether was then added and the mixture was filtered through a pad of silica and the silica was washed with EtOAc:toluene 20:80 to yield 40.35 g (70%) of the pure title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19](=O)[CH3:20])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>>[CH3:22][C:23]([S@:26]([NH:28][CH:19]([C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1)[CH3:20])=[O:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Oc2ccc(C(F)(F)F)nc2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(C(F)(F)F)nc1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (1.67 g, colorless amorphous) from 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone (1.69 g, 5.70 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.56 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2cccs2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)s2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc-hexanes) gave the product as a yellow solid (0.122 g, 46% yield). MS: m/z 532.4 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl>CN(C=O)C>[CH2:30]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][CH:12]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a thoroughly degassed suspension of K2CO3 (127 g, 921 mmol) in DMF (600 mL) was added methyl-4-hydroxybenzoate (70 g, 461 mmol) and the mixture heated to 70° C. after which was added bromododecane (126 g, 507 mmol) and the reaction allowed to stir at 70° C. under argon for 3 hours, after which TLC (CH2Cl2) showed completion. Reaction was cooled to room temperature and precipitated into cold water. The precipitate was collected by suction filtration and purified by re-crystallization from acetone to give the title compound (140 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C.C(OCC)C>[CH2:25]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:17]=1[CH2:16][CH2:15][N:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][N:12]=1)[CH2:35][CH3:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)-amino]-5-pyridinecarboxylate (850 mg), and sodium hydride (101 mg, 50% dispersion in oil) in DMF (20 ml) was stirred for 15 minutes then iodoethane (150 ml) was added and the mixture stirred for 2 hours. The mixture was diluted with diethyl ether (50 ml) washed with water, dried (MgSO4), filtered through silica gel, evaporated and the residue re-dissolved in dichloromethane and evaporated to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridine carboxylate (800 mg).