Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=[CH:34][C:29]=2[N:28]=N1.C(N(CC)CC)C.[NH2:42][C:43]([C:45]1[C:53]2[CH2:52][CH2:51][C:50]3[CH:54]=[CH:55][C:56]([NH:58][C:59](=[O:67])[C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[Cl:66])=[CH:57][C:49]=3[C:48]=2[N:47]([C:68]2[CH:73]=[CH:72][C:71](/[CH:74]=[CH:75]/[C:76](O)=[O:77])=[CH:70][CH:69]=2)[N:46]=1)=[O:44]>CN(C)C=O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[C:59]([NH:58][C:56]1[CH:55]=[CH:54][C:50]2[CH2:51][CH2:52][C:53]3[C:45]([C:43]([NH2:42])=[O:44])=[N:46][N:47]([C:68]4[CH:73]=[CH:72][C:71](/[CH:74]=[CH:75]/[C:76]([NH:28][CH2:29][CH2:34][O:8][CH3:4])=[O:77])=[CH:70][CH:69]=4)[C:48]=3[C:49]=2[CH:57]=1)=[O:67]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1nn(-c2ccc(/C=C/C(=O)O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Reactant: On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)/C=C/c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1

Procedure:
To a 4 mL peptide flask was added 100 mg of the resin. A solution of HBTU (127 mg, 0.336 mmol), 1-hydroxybenzotriazole (52 mg, 0.38 mmol), triethylamine (34 mg, 0.34 mmol), and (2E)-3-(4-{3-(aminocarbonyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazol-1-yl}phenyl)prop-2-enoic acid (172 mg, 0.335 mmol) in 2mL of N,N-dimethylformamide was added to the resin. The peptide flask was agitated on an orbital shaker for 16 hrs, after which the solution was drained and the resin was washed with DMF, dichloromethane, and diethyl ether. The resin was dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10](=O)[CH2:11][CH3:12].[Si]([C:18]#[N:19])(C)(C)C>C(#N)C.O.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:10]([CH3:9])([CH2:11][CH3:12])[C:18]#[N:19])=[N:6][CH:7]=1
Reactant: CCC(C)=O
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: O
Product: CCC(C)(C#N)Nc1ccc(Br)cn1
Temperature: 0 °C

Procedure:
A mixture of 5-bromopyridin-2-amine (500 mg, 2.89 mmol), butan-2-one (611 μl, 6.82 mmol), and zinc chloride (0.5 M, 1.15 mL, 0.578 mmol) in acetonitrile (1.44 mL) was purged with Ar(g) for ˜5 minutes. The reaction was cooled to 0° C. and TMS-CN (775 μl, 5.78 mmol) was added dropwise. The reaction mixture was heated to 85° C. overnight. Upon cooling, the reaction mixture was diluted with water and extracted with dichloromethane (3×). The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield 2-[(5-bromopyridin-2-yl)amino]-2-methylbutanenitrile. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=3.2, 1H), 7.49 (dd, J=2.6, 8.9, 1H), 6.46 (d, J=9.6, 1H), 4.74 (s, 1H), 2.11-1.95 (m, 2H), 1.69 (s, 3H), 1.10-1.06 (m, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([C:14]2[CH:13]=[CH:12][C:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: CCCCCCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a 2 L three-necked flask, set up with a mechanical stirring, containing AlCl3 (85.661 g; 642.42 mmol) under N2, 4-hexylbenzene (IVb) (104.25 g; 642.42 mmnol) was added in one portion at room temperature. To this resulting orange suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (125.000 g; 535.35 mmol) was added drop wise during 45 minutes without cooling. Then reaction mixture was stirred for 3 h until temperature cooled down to room temperature, time when no more foaming was observed. The deep brown mixture was then stirred at room temperature overnight. The black thick solution was poured under stirring into a mixture of ice and 1N HCl (800 mL), then the resulting white-orange solid was filtered, and washed successively with water, saturated solution of NaHCO3 and finally with water until pH of the filtrate was 7. The solid was washed with heptane (3×200 mL) and dried under vacuum at room temperature to give the title compound as a white powder (m=151.15 g) in a 79% yield. Melting point: 108° C.
Reaction SMILES: C([C@H:3]([CH2:18][CH2:19][CH2:20][CH2:21]CC1C=CC(O)=CC=1)[CH:4]=[C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11]C(C)(C)C)=[O:10])=[CH:7][CH2:6]1)#N.[OH-:30].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].Cl>O.C(O)C>[CH3:36][O:35][C:33]([O:30][C:19]1[CH:18]=[CH:3][C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:16][CH:17]=2)=[CH:21][CH:20]=1)=[O:34]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)C1=CCC(=C[C@H](C#N)CCCCCc2ccc(O)cc2)C=C1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
4'-Hydroxy-4-biphenylcarboxylic acid (3) (4 g, 18.67 mmol) and sodium hydroxide (1.64 g, 41.1 mmol) were dissolved in water (50 ml) and ethanol (98 ml) at -10° C. To the solution, methyl chloroformate (1.73 ml, 22.4 mmol) was added and the solution was maintained at -5° C. The solution was stirred for 40 minutes and a mixture of water and hydrochloric acid (1:1) was added until the solution became acidic. The solid precipitate was collected by vacuum filtration, washed several times with distilled water and dried to yield 4.72 g (yield 95.5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[C:14]([S:20](=[O:21])(=[O:22])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH:13]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Nc2ccccc2O)c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A solution of 2-aminophenol (2.5 g, 22.9 mmol) in dry methylene chloride (10 mL) was added to a mixture of 4-bromo-3-chlorosulfonyl-5-methyl-benzoic acid methyl ester (7.18 g, 22.9 mmol) and dry pyridine (10 mL, 124.7 mmol) in methylene chloride (40 mL). The reaction mixture was stirred for 1 h at 10° C. and at room temperature overnight. It was concentrated, treated with 10% HCl (100 mL) and extracted with 1-butanol. The organic layer was washed with water, brine, dried, concentrated, treated with methanolic HCl (60 ml) and refluxed for 3 h. The reaction mixture was concentrated, treated with 10% aqueous sodium bicarbonate solution to alkaline pH and extracted using ethyl acetate. The organic layer was washed with water, brine, dried and purified, using flash chromatography (silica gel, 10% ethyl acetate/pet ether) to obtain the title compound. Yield: 2.2 g, (24%); 1H NMR (CDCl3): δ 2.4 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 6.6 (t, 1H, Ar), 6.72 (t, 1H, Ar), 6.74 (d, 1H, Ar), 7.2 (d, 1H, Ar), 7.94 (s, 1H, OH), 7.96 (s, 1H, Ar), 8.5 (s, 1H, Ar); MS: m/e (EI+) 400 (M+1).
Reaction SMILES: O[CH:2]1[C:10]2[N:6]([C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:8]3[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH3:18])[C:9]3=2)[C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.[CH3:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1>C(#N)C.[Au](Cl)(Cl)Cl>[CH3:18][N:11]1[C:9]2=[C:10]3[N:6]([C:7]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:8]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]1=[O:17])[C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH:2]3[C:32]1[O:31][C:30]([CH3:29])=[CH:34][CH:33]=1
Reactant: COC(=O)[C@@H]1CCC(O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Reactant: Cc1ccco1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1CCC(c2ccc(C)o2)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Gold (III) chloride (0.142 g, 0.469 mmol) was added to a solution of (7S)-methyl 10-hydroxy-1,3-dimethyl-2,4-dioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylate (1.8 g, 4.69 mmol) and 2-methylfuran (0.466 mL, 5.16 mmol) in acetonitrile (30 mL). The mixture was stirred at room temperature for 25 mins, then quenched with saturated NaHCO3(aq). The mixture was extracted with DCM, the organic phase passed through a hydrophobic frit and evaporated under vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11](/[CH:12]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A mixture of 3-benzyloxy-benzaldehyde (5.16 g, 24.3 mmol) described in Manufacturing Example 61-1-1, nitromethane (2.16 mL, 48.6 mmol), ammonium acetate (2.81 g, 36.5 mmol) and acetic acid (50 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (5.50 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C-]#N.[CH3:18][N:19](C=O)C>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1COCC1>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]#[N:19])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: [Fe+2]
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 110 °C
Reaction time: 21 h
Yield: 84 %

Procedure:
Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zink cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.N1C=CC=CC=1.O>[N:13]1[N:14]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=[C:9]2[CH:10]=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ccc2cncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccc2cncnn12
Temperature: 70 °C
Yield: 43.9 %

Procedure:
A mixture of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester (40 mg) and an aqueous solution of sodium hydroxide (6 M, 1 mL) in a mixture of tetrahydrofuran and methanol (1/1, 1 mL) was heated at 70° C. for 1 hour. The reaction mixture was then cooled, acidified by addition of an aqueous solution of hydrochloric acid (6 M) and evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and water (10/1, 5.5 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 15 mg of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:19][C:18]2[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH3:16])[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2c(C)cc(C)cc2C)n1
Yield: 44.1 %

Procedure:
A mixture of 5.3 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 2.7 g of 2,4,6-trimethylaniline and 2.1 g of sodium carbonate in 50 ml. of ethanol was heated in an autoclave to 200°C. for 5 hr. The reaction mixture was filtered and water was added to initiate precipitation. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 3.2 g of product, mp. 100-103°C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH3:21]>CS(C)=O>[CH3:22][CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][CH2:16][C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCC(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(CCCC(C)CC)C(=O)OCC
Yield: 95.5 %

Procedure:
First, 4 g (0.1 mol) of NaH as an oil was added to 100 mm of dried DMSO, forming a mixture. Into this mixture, 17.4 g (0.1 mol) of diethyl methylmalonate was dripped, while being stirred on an ice bath. Then, 13.4 g (0.1 mol) of 1-chloro-4-methylhexane was added to the resultant mixture and reacted with it at 70° C. for five hours. thereby obtaining 26 g of crude diethyl 4-methylhexylmethylmalonate (II). This reaction is described as follows: ##STR3##
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]4[C:4]5[C:9](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate, 26.5 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 6.9 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 24.2 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 9.3 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)=[O:9]>C(#N)C>[ClH:6].[I:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=1
Reactant: CC(C)(C)N
Reactant: O=C(CCl)c1ccc(I)cc1
Solvent: CC#N
Product: CC(C)(C)NCC(=O)c1ccc(I)cc1
Product: Cl
Temperature: 20 °C

Procedure:
A solution of tert-butylamine (154 ml) in acetonitrile (100 ml) was added over 10 minutes to a solution of 2-chloro-4'-iodoacetophenone (158.0 g, prepared as described in Organic Magnetic Resonance 12 (12), 1979 pages 691-695) in acetonitrile (700 ml) with stirring under nitrogen at 20° C. The mixture was warmed to 30° C. whereupon a solution was formed, then a slight exotherm occurred and tert-butylamine hydrochloride precipitated. The mixture was kept below 37° C. by occasional cooling. The mixture was left stirring at ambient temperature for 18 hours then filtered and the residue washed with acetonitrile. The combined filtrate and washings were reduced in volume and then taken up in a mixture of ether (700 ml) and water (500 ml). The mixture was stirred while the pH was adjusted to 9 using dilute hydrochloric acid. The mixture was filtered to remove tert-butylamine hydrochloride. The filtrate was acidified with dilute hydrochloric acid to give 4'-iodo-2-(tert-butylamino)acetophenone hydrochloride (102.0 g). This product was reacted with malononitrile (29.9 g) and potassium hydroxide (52.3 g) in methanol (1.5 l) and water (100 ml) in a similar manner to Example 2, to give 2-amino-3-cyano-4-(4-iodophenyl)-1-(tert-butyl)pyrrole (63.2 g), m.p. 166.5-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12]O.[BrH:14].[Br-].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.C(Cl)Cl.C1C=CC=CC=1>[Br-:14].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc([N+](=O)[O-])ccc1CO
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 84 %

Procedure:
Bromination of (2-methoxy-4-nitrophenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the conditions for the displacement were 3 days at 20° C. followed by 1 day at 55° C., gave the phosphonium salt (582) (84%) as a yellow solid, mp (CH2Cl2/benzene) 194–196° C. 1H NMR (CDCl3) δ 7.83–7.63 (m, 17H), 7.45 (br s, 1H), 5.52 (d, J=15.0 Hz, 2H). Found: C, 61.10; H, 4.73; N, 3.05. C26H23BrNO3P requires C, 61.43; H, 4.56; N, 2.76.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]C1C=CC=CC=1C(C1C=CC=CC=1)=O>>[Br:17][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][NH2:9]
Reactant: O=C(c1ccccc1)c1ccccc1Br
Reactant: Cc1ccccc1C(CN)c1ccccc1
Product: NCC(c1ccccc1)c1ccccc1Br

Procedure:
The title material was prepared as described for the synthesis of 2-phenyl-2-o-tolylethanamine (Example FF) in using (2-bromophenyl)(phenyl)methanone. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.15 (2H, dd, J=7.45, 2.65 Hz) 4.36 1H, (t, J=7.45 Hz) 7.12-7.20 (2H, m) 7.22-7.29 (5H, m) 7.38 (1H, td, J=7.52, 1.14 Hz) 7.48 (1H, dd, J=7.71, 1.64 Hz) 7.58 (1H, dd, J=7.83, 1.26 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[C:13](=[O:16])([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:12][N:2]([CH3:1])[CH:3]([C:5]1[CH:6]=[C:7]([O:11][C:13](=[O:16])[N:2]([CH2:3][CH3:4])[CH3:1])[CH:8]=[CH:9][CH:10]=1)[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(c1cccc(O)c1)N(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(C)C(=O)Oc1cccc(C(C)N(C)C)c1
Reaction time: 35 h

Procedure:
The process of the present invention for example involves reacting 3-[1-(dimethylamino)ethyl]phenol with N-ethyl-N-methyl-4-nitrophenyl carbamate in the presence of potassium carbonate and dimethyl sulfoxide at a temperature ranging from about 80° C. to about 120° C. for about 30 to 40 hours, to form racemate of ethylmethylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester in the free base form. This racemate is then resolved to obtain the (S)-ethylmethylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester. The preferred method of resolution of the (S)-isomer from the racemate involves dissolving a mixture of the free base of the racemate and (+)-di-O, O′-p-toluoyl tartaric acid monohydrate in a 2:1 mixture of methanol:water by heating, collecting the precipitate on cooling by filtration, crystallizing the precipitate from a 2:1 mixture of ethanol:water, and obtaining the substantially pure (S)-isomer by partitioning it between 1N sodium hydroxide and a suitable organic solvent. The base may further be converted to its pharmaceutically acceptable acid addition salts, such as L(+)-tartrate salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[CH3:22][O-:23].[Na+].CO.[Na]>C(OCC)(=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:23][CH3:22])[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:5]=1
Reactant: C[O-]
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3ccccc3F)n2)n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2ccccc2F)nc(-c2cccc(C)n2)n1
Reaction time: 1 h

Procedure:
To the mixture of 4-chloro-6-o-fluoro phenyl-2-(6-metyl-2-pyridinyl)pyrimidine (1 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.1 g). After the mixture was left to stand at room temperature for 1 hour, water (30 ml) and ethyl acetate (100 ml) were added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 4-o-fluorophenyl-6-methoxy-2-(6-methyl-2-pyridinyl)pyrimidine (0.82 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (32 g, 74.2 mmol) and Et3N (22.5 g, 226 mmol) in CH2Cl2 (400 mL) was added a solution of MsCl (10.1 g, 89 mmol) in CH2Cl2 (50 mL) at 0-5° C. After addition, the reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was washed with water (200 mL) and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layers was washed with 10% citric acid (60 mL), sat. NaHCO3 (60 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 100%), which was used in the next step without purification.