Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C@@H:11]1([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:18][CH2:17][C@H:16]2[O:19][C@@H:11]([N:20]3[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]3=[O:22])[C@H:12]([OH:13])[C@@H:14]2[OH:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)cc1

Procedure:
4-Methylbenzoyl chloride (10 mmol) is added to a solution of uridine (10 mmol) in 20 mL of pyridine. After no further progress occurs as observed by TLC, the volatile components are evaporated in vacuo. The residue is purified using flash chromatography to give the product as a colorless oil.
Reaction SMILES: CN(C)C1C=CC([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=[O:12])=O)=CC=1.C(N(CC)C1C=CC=C(N(CC)CC)C=1)C.C(OC(=O)C)(=O)C>CO>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([Cl:20])[C:14]([Cl:21])=[C:10]2[C:9]=1[CH2:7][O:12][C:11]2=[O:13]
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during 2 hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis-(diethylamino)phenyl)-3-(4-dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = (CH3CH2)2N, Y2 = H, Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) in three fractions (m.p. 174°-176° C., m.p. 180°-181° C. and m.p. 180°-181° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18](=[O:33])([O:26]C1C=CC=CC=1)[O:19]C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC(C(O)=O)=CC=1.C1C=CC(C([O-])=O)=CC=1.C(OC1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH3:9].[C:18]([OH:33])([OH:26])=[O:19]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)c1ccccc1
Product: O=C(O)O
Temperature: 160 °C

Procedure:
0.20 mol bisphenol A, 0.21 mol diphenyl carbonate, 3×10-6 mol tetrabutyl ammonium bibenzoate and 4×10-3 mol phenyl benzoate are taken in a 250 ml glass reactor equipped with stirrer, nitrogen inlet and distillation assembly. Under the blanket of nitrogen the contents in the reactor were heated by means of thermostatically controlled furnace to 160° C. for 11/2 hr. Subsequently, the temperature was increased to 230° C. and pressure reduced from atmospheric to 100 mm Hg, and on keeping constant the temperature and pressure for one hour, about 80% phenol was collected. Maintaining the temperature at 230° C., the pressure was decreased sequentially in a following way: 80 mm, 1/2 hour; 60 mm, 1/2 hour; 40 mm, 1/2 hour; 20 mm, 1/2 hour; 10 mm, 1/2 hour and 1 mm, 1/2 hour. It was then observed that phenol removal was almost quantitative. Finally reaction mixture was heated to 280° C. at 1 mm for one hour to remove any residual phenol. The polymer, bisphenol A polycarbonate obtained in 99% yield was colorfree and its relative viscosity measured in chloroform at 25° C. in an ubbelohde viscometer was 1.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32])#[N:21].N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:33])=[O:32])#[N:21]
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: N#CCC=Cc1ccccc1S(N)(=O)=O
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CCC#N)n1
Reaction time: 15 h
Yield: 66.9 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate are added to a solution of 4.45 g of 2-(3-cyano-1-propen-1-yl)phenylsulfonamide and 3.3 ml of 1,5-diazabicyclo[5,4,0]undec-5-ene in 80 ml of dioxan, and the mixture is stirred for 15 hours at 20°-25° C. The reaction mixture is then taken up in 350 ml of water and the aqueous solution is acidified to pH 2 with 2N HCl and extracted with ethyl acetate. The organic extracts are combined and concentrated. The oily orange-coloured residue is dissolved in a very small amount of acetone. About 20 ml of diethyl ether are added to this solution, which is diluted dropwise with hexane until the onset of crystallisation. The mixture is subsequently further cooled and the precipitated crystals are isolated by filtration. Yield: 5.2 g of the title compound with a melting point of 142°-143° C.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N+:13]([O-:18])[C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].O.[CH2:30]=[C:31]1[O:35][C:33](=[O:34])[CH2:32]1>CC(C)=O>[C:33]([NH:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N+:13]([O-:18])[C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12)(=[O:34])[CH2:32][C:31]([CH3:30])=[O:35]
Reactant: Cc1ccc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n[n+]1[O-]
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(C)[n+]([O-])n3)CS[C@H]12

Procedure:
A mixture of 0.354 g. of 7-amino-3-(6-methyl-1-oxidopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid, 0.42 g. of sodium hydrogen carbonate, 5 ml. of water and 5 ml. of acetone is cooled to 5° C and under stirring, 0.2 g. of diketene is added. The mixture is further stirred at room temperature for 30 minutes. The acetone is distilled off under reduced pressure and the residue is washed with ethyl acetate. The water layer is separated, brought to pH 2 with 50 % phosphoric acid, saturated with sodium chloride and extracted three times with ethyl acetate. The extracts are pooled, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated and allowed to stand under cooling with ice. The resultant crystals are loosened with the addition of ether and recovered by suction-filtration. The procedure gives 7-acetoacetamido-3-(6-methyl-1-oxidopyridazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 85°-87° C(decomp.). Yield 0.13 g. (30 %).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[O:15]C)[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClCCCl.O>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15])[CH3:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1OC
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
(2-Methoxy-4-nitrophenyl)-carbamic acid ethyl ester (2.15 g) was dispensed in 1,2-dichloroethane (20 mL) and cooled to 0° C. Boron tribromide (2.0 mL) in 1,2-dichloroethane (10 mL) was added dropwise. The reaction mixture was stirred 10 minutes at 0° C. and 30 minutes at room temperature. The mixture was again cooled to 0° C., and water (10 mL) was added carefully. The reaction mixture was neutralised with saturated aqueous sodium bicarbonate and aqueous hydrochloric acid (5M). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with water (2×100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as brownish solid (1.96 g, 97%).
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH3:14])[N:10]=[C:9]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:8]=1)=[CH2:6])C.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[N:8]=[C:7]([C:5](=[O:4])[CH3:6])[CH:12]=[C:11]([CH:13]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH3:14])[N:10]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: C=C(OCC)c1cc(C(C)OCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C(C)=O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 40 °C

Procedure:
Concentrated hydrochloric acid (0.202 mL, 2.39 mmol) was added to a solution of 4-(1-ethoxy-vinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-(1-(2,2,2-trifluoroethoxy)ethyl)-pyrimidin-2-amine (0.38 g, 0.80 mmol) in dioxane (30 mL) and water (3 mL). The solution was heated at 40° C. for 0.5 h, cooled and neutralised with sodium bicarbonate (1 g). Brine was added (5 mL) and the water phase was extracted with ethyl acetate (2×10 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using a gradient 0-4% methanol in dichloromethane as eluent to give the title compound, 330 mg (92%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[CH:11][C:10]=2[N:9]=1>ClCCl>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:20]([CH2:21][C:22]([NH:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])([CH3:23])[CH3:24])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
Isopropyl isocyanate (190 μL, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-1-isopropylurea (0.90 g, 1.75 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature. A precipitate formed and the mixture was stirred over the weekend. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica gel, gradient elution with 8-10% methanol in dichloromethane) to provide a solid that was dried under vacuum at 60° C. to yield 0.34 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[(6-{[(isopropylamino)carbonyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)-N′-1-isopropylurea as a tan solid, mp 205-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[C:11]=1[F:12].[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([S:10][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)[NH:7][C:6]=2[C:11]=1[F:12]
Reactant: Fc1ccc2nc(S)[nH]c2c1F
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccc(F)c(F)c3[nH]2)o1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
6,7-Difluoro-1H-benzimidazole-2-thiol (0.34 g, 1.81 mmol) is suspended into 20 mL of tetrahydrofuran (THF) under argon. Then, 130 mg (2.71 mmol) of sodium hydride are added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.25 g, 1.81 mmol) is then added and the reaction mixture is stirred at room temperature for 3 h, upon which it is poured on ice and extracted twice with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 70 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/THF from 100/0 to 80/20 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a prepacked 30 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 100/0 to 95/5 v/v; rate: 20 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 0.28 g of 5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a pale yellow meringue. LCMS-DAD-ELSD: 281(+): [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[N:29]2[N:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[N:33][C:28]2=[N:27][CH:26]=1>>[OH:37][C:34]([C:32]1[CH:31]=[N:30][N:29]2[C:25]([C:9]3[CH:10]=[C:11]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:26][N:27]=[C:28]2[N:33]=1)([CH3:36])[CH3:35]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 29 %

Procedure:
3′-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (see Example 1, step c) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 29% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 166° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.50 (1H, br s), 7.49-7.71 (5H, m), 7.83 (1H, m), 8.10 (1H, m), 8.27 (1H, s), 8.31 (1H, m), 8.79 (1H, s); MS (ES+) m/z 356 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3C[C@H](NC(=O)CO)[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH:6]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H:56]([NH:58][C:59]([CH2:61][O:62]C(=O)C)=[O:60])[C@@H:55](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH2:56]([NH:58][C:59]([C@@H:61]1[C@@H:18]([OH:26])[C@@H:17]([OH:27])[C@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:5]2[CH:6]=[C:2]([NH2:1])[CH:3]=[N:4]2)=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:62]1)=[O:60])[CH3:55]
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(N)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP), by substituting (2S,3S,4R,5R)-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide (Intermediate ZY) for acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in step ZP1.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:10]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=S(=O)(O)O
Product: CC(C)C(C)(N)C(N)=O

Procedure:
In a similar way, hydrolysis of the (+)-2-amino-2,3-dimethylbutyronitrile with sulfuric acid yields (+)-2-amino-2,3-dimethylbutyramide, mp 74.5°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11](C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:54])([F:53])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:14]=[C:13]([C:43]2[CH:42]=[CH:41][C:40]([C:39]([F:54])([F:53])[F:38])=[CH:45][CH:44]=2)[CH:12]=[C:11]([C:42]2[CH:41]=[C:40]([C:39]([F:54])([F:53])[F:38])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3,5-bis-trifluoromethylphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Brc1cccs1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccs2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromothiophene (60 μL, 0.62 mmol) according to the general procedure IF to give 97 mg (71%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.44 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.50-7.39 (m, 2H), 7.31-7.23 (m, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.00 (dd, J=5.1, 3.7 Hz, 1H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.1, 131.8, 131.6, 128.4, 127.1, 127.1, 123.4, 120.9, 92.9, 82.3, 51.6, 35.3, 30.8; ESI-MS m/z 293.1 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2ccccc2c1-c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2ccccc2c1-c1cccc(CO)c1

Procedure:
A solution of 13.2 g (50 mmol) of 3-(2-aminonaphthalen-1-yl)benzoic acid in 300 ml of THF is added dropwise to a solution of 3.8 g (100 mmol) of lithium aluminium hydride in 500 ml of THF. When the addition is complete, the mixture is stirred under reflux for a further 2 h and allowed to cool, 4 ml of water, 4 ml of 15% by weight NAOH solution and 12 ml of water are then added dropwise, the mixture is stirred for a further 30 min., the precipitated salts are filtered off with suction and washed three times with 100 ml of THF each time, and the THF is removed in vacuo. Yield: 11.2 g (90 mmol), 89.8%; purity according to 1H-NMR about 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccnc(Cl)c1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 400 mg (1.85 mmol) of 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 1.12 ml (1.46 g, 11.1 mmol) of 2-chloro-4-fluoropyridine in 5 ml of DMF were added 1.2 g (3.69 mmol) of cesium carbonate. The mixture was heated to 100° C. for 4 h, allowed to cool and concentrated in vaccuo. The residue was taken up in 20 ml ethyl acetate and the organic phase was washed twice with 20 ml of water and dried over magnesium sulfate. After treatment with charcoal, the solution was filtered and concentrated to yield 531 mg (1.62 mmol, 88%) of the title compound as an off-white crystalline solid, MS: m/e=328.1, 330.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH2:11][CH3:12]
Reactant: N#Cc1cccc(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzonitrile (11.052 gm; 92.8 mmol), n-propyl bromide (24.4 gm; 198 mmol), and potassium carbonate (38.65 gm; 280 mmol) in 2-butanone (175 mL) and heat and reflux. After 17 h., cool the mixture to room temperature, and decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine the organic layers and wash with water, 1 N NaOH, and water, dry over MgSO4, and concentrate. Distill the residue to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:22]=[CH:21][C:20](OC)=[C:19](OC)[CH:18]=2)=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1C=CC=CC=1)=O.CC(P(OC)(O)=O)(C([O-])=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: COc1ccc(C(=O)c2ccccc2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: COC(=O)C=C(c1ccccc1)c1ccc(OC)c(OC)c1

Procedure:
Methyl 3-(3,4-Dimethoxyphenyl)-3-phenylacrylate was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxybenzophenone (4.8 g, 20 mmol), trimethylphosphonoacetate (4.1 g, 22 mmol) and lithium hexamethyldisilazide (22 mL, 22 mmol, 1 M) with a reaction time of 138 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 14.39 g (73%) of a mixture of the E and Z isomers as an oil. The isomers were separated by additional purification (silica gel, 1% ethyl acetate/methylene chloride) to afford pure samples of each of the isomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([N:21]=[N+]=[N-])[C@H:11]([N:12]=[N+]=[N-])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]>C(O)(=O)C.O.[C].[Pd]>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[C@H:11]([NH2:12])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)[C@]1(N)[C@H](N)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
25 mg of 10% palladium carbon was added to 170 mg of (1R,2R,3R,5R,6R)-2,3-diazido-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in a mixture of 15 mL of acetic acid and 5 mL of water, and the mixture was stirred for 24 hours at room temperature under a hydrogen atmosphere. After celite filturation, the solvent was distilled off at 50° C. under reduced pressure, thereby yielding 42 mg of (1R,2R,3R,5R,6R)-2,3-diamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.