Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:4]=1.C1COCC1>Cl.O1CCOCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Reaction time: 20 h
Yield: 130.6 %

Procedure:
A solution of tert-butyl {1-[4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (1.07 g, 3.09 mmol) in HCl in Dioxane (4M, 5 mL) and THF (5 mL) was stirred at rt for 6.5 h. HCl in Dioxane (4M, 2 mL) was added and the reaction mixture was stirred for another 20 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.99 g, 100%) as a solid. 1H NMR (500 MHz, CD3OD): 8.19 (d, 1H), 7.82 (s, 1H), 7.22 (d, 1H), 4.64 (d, 2H), 3.66-3.56 (m, 1H), 3.52 (td, 2H), 3.29 (d, 2H), 1.87 (dq, 2H); 13C NMR (CD3OD): 152.6, 144.8, 144.5, 144.2, 143.9, 138.7, 125.3, 123.1, 120.9, 118.7, 111.2, 108.1, 45.3, 29.0; Mass Spectrum: M+H 246
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=2)=[O:13])=[CH:7][C:6]=1[O:31][CH3:32].[NH2:33][CH2:34][CH2:35][OH:36].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(#N)C>[C:27]([CH:24]1[CH2:25][CH2:26][CH:21]([C:17]2[CH:16]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:33][CH2:34][CH2:35][OH:36])=[C:6]([O:31][CH3:32])[CH:7]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: NCCO
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCBr
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCNCCO
Yield: 88.5 %

Procedure:
Intermediate 5 (200 mg), 2-aminoethanol (122 mg) and triethylamine (45 mg) are dissolved in acetonitrile (5 ml), and the mixture is heated under reflux for 18 hours. To the reaction solution is added chloroform, and the mixture is washed with water. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 20% chloroform/methanol) to give the desired compound (170 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O.[OH2:19]>CS(C)=O>[Br:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)[OH:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(CC)cn1
Reactant: O
Solvent: CS(C)=O
Product: CCc1ccc(C(O)CBr)nc1
Reaction time: 0.5 h

Procedure:
To a solution at −5° C., of 50 g (0.3759 mol) 5-ethyl-2-vinyl-pyridine dissolved in a mixture of 2504 mL dimethylsulfoxide and 13.5 mL water was added 99.3 g (0.5578 mole) N-bromosuccinimide and stirring was continued for 30 min. at 0 to −5° C. Reaction mixture was quenched with 2500 mL water and the product was extracted with dichloromethane. Organic layer was dried (calcium chloride); concentrated and purified to get the desired product. Yield of the product was 76.09 g (88%). The two side products in this reaction found were 2-acetyl-5-ethyl-pyridine (5%) and 2-(1-bromo vinyl)-5-ethyl-pyridine (6%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][O:9][N:10]=[C:11]1[C:14]([CH3:16])([CH3:15])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3]C)=[O:2].[Li+].[OH-]>C1COCC1.CO.CCOC(C)=O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][O:9][N:10]=[C:11]1[C:14]([CH3:15])([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1cccc(CON=C2C(c3ccccc3)=C(c3ccc(S(C)(=O)=O)cc3)C2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C(=NOCc2cccc(C(=O)O)c2)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of methyl ester from Example 52 (90 mg) in THF (2 mL) and MeOH (1 mL) was treated with LiOH (2N, 276 μL ). The mixture was heated at reflux for 18 hr, cooled to r.t. and diluted with EtOAc and HCl 1N. The organic phase was washed with brine, dried (MgSO4) and the solvent evaporated to give the title compound as white foam; 1H NMR (300 MHz, Ace-d6): δ 1.64 (s,6H), 3.17 (s, 3H), 5.26 (s, 2H), 7.39 (m, 3H), 7.51 (t, 1H), 7.70 (m, 3H),7.86 (d, 2H), 8.0 (m, 3H), 8.15 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:19])[CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol) in dry DCM (10 mL) was added trifluoroacetic acid (3.42 mL, 3 mL/mmol. The reaction mixture was stirred at r.t. for 2 h. After completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed under vacuo to afford trifluoroacetic acid salt of 1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (295 mg, 93%) as a gummy solid. The crude compound was used as such without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[C@H:19]([OH:22])[CH2:20][OH:21])=[CH:4][CH:3]=1.C(Cl)Cl.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:21][CH2:20][C@H:19]([C:9]1[C:10]([CH3:18])=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:22])(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-1-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane-1,2-diol (3G) (0.981 g, 3.14 mmol) in pyridine (5.0 mL)/DCM (15.0 mL) was added pivaloyl chloride (0.463 mL, 3.77 mmol). The reaction mixture was stirred for 5 h at room temperature and diluted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 3H as a white solid (1.296 g). 1H-NMR: 300 MHz, (CDCl3): δ: 7.72 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.46-7.37 (m, 3H), 7.26-7.10 (m, 4H), 4.99 (dd, J=8.7, 3.0 Hz, 1H), 4.45 (dd, J=11.7, 9.7 Hz, 1H), 4.13 (dd, J=11.7, 3.3 Hz, 1H), 2.72 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>C1COCC1.O>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C1N(c2ccc(O)cc2)CCCCN1c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N2CCCCN(c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one (26 mg) was dissolved in THF (2 mL), and sodium hydride (80% in oil, 3 mg) was added. After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 11 mg) was added. After 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 445.57 (C27H31 N3O3); MS (ESI): 446 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]([CH3:15])[C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCC1=O.C1COCC1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)/[N:11]([CH3:15])[C:10]2=[O:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Temperature: 65 °C
Yield: 86.3 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C18H11Cl2N3O2: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([Cl:13])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]1[C:23]2([CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21][NH:20]1>C(#N)C>[ClH:13].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:20]3[CH2:21][CH2:22][C:23]4([CH2:27][CH2:26][NH:25][CH2:24]4)[CH2:19]3)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CC2(CCNC2)CN1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCNC4)C3)nc21
Product: Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 33.4 %

Procedure:
A suspension of of 1.10 g (4.00 mmol) 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 40 ml acetonitrile was treated with 1.10 g (8.7 mmol) 2,7-diazaspiro[4.4]nonane and the mixture was stirred at room temperature 4.5 hours. A crude solid was filtered, stirred with 10 ml water, filtered, dissolved in 100 ml 6M ammonium hydroxide and lyophilized to afford 0.53 g of solid. This was dissolved in dilute hydrochloric acid, filtered, lyophilized and crystallized from ethanol-water to give 0.26 g of the title compound, mp>300° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C@H:4]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=O.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH2:21].C(Cl)CCl>ClCCl.CCOC(C)=O>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH:21][C:5](=[O:7])[C@H:4]([CH2:3][CH:2]([CH3:1])[CH3:13])[C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)O
Reactant: NOC1CCCCO1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a stirred solution of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid (6.0 g, 32.3 mmol) in 33 mL of dichloromethane at 0° C. is added 2-tetrahydropyranyloxyamine (7.70 g, 65.8 mmol) followed by EDC (7.50 g, 39.4 mmol). The reaction mixture is allowed to warm to 25° C., stirred 12 h, then diluted with 100 mL of EtOAc and washed successively with 50 mL each of water, 1 M aqueous sodium bisulfate solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The combined organic layers are dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc-hexanes affords 9.0 g (97%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a gum.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[OH-:15].[Na+:16].[S:17]([O-:20])([OH:19])=[O:18].[Na+]>[Cu]Cl>[C:7]([C:6]1[S:5][C:4]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:3]=2[C:2]=1[S:17]([O-:20])(=[O:19])=[O:18])([OH:15])=[O:8].[Na+:16]
Reactant: O=S([O-])O
Reactant: Cc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: [OH-]
Agent: Cl[Cu]
Agent: [Na+]
Product: Cc1ccc2c(S(=O)(=O)[O-])c(C(=O)O)sc2c1

Procedure:
Prepared analogous to Example 1(a) from 3-chloro-6-methyl-benzo[b] thiophene-2-carboxylic acid chloride (m.p.: 124.5°-126° C.) by hydrolysis with aqueous sodium hydroxide solution and subsequent reaction with sodium hydrogen sulfite in the presence of copper-(I)-chloride as a catalyst.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([N:61]=[N:62][C:63]2[CH:76]=[CH:75][C:66]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]O)=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53].O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][O:67][C:66]2[CH:65]=[CH:64][C:63]([N:62]=[N:61][C:58]3[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=3)=[CH:76][CH:75]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(OCCCCCCO)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCCCCCOc3ccc(N=Nc4ccc([N+](=O)[O-])cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
0.2 g of N,N'-dicyclohexyldicarbodiimide (DCC) was added at room temperature while stirring to a solution of 0.5 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.25 g of 6-[4-(4-nitrophenylazo)phenoxy]hexanol and 0.04 g of 4-dimethylaminopyridine (DMAP) in 25 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol 1:1) and two-fold recrystallization from acetone of the fractions which were pure according to thin-layer chromatography gave 0.4 g of 6-[4-(4-nitrophenylazo)phenoxy]hexyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate; m.p. (C-N) 72° C., cl.p. (N-I) 127° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)COC(C(C)(C)c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 mL THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[O:16]1[C:15]2([CH2:14][CH2:13][CH:12]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:21][CH2:20]2)[O:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Ic1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (prepared according to U.S. Pat. No. 4,360,531) (2.0 g, 6.4 mmol), 4-iodopyrazole (1.36 g, 7.0 mmol), K2CO3 (1.06 g, 7.7 mmol), and 18-crown-6 (0.2 g, 0.7 mmol) in DMF (5 mL) was heated under nitrogen at 50° C. for 16 h. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (3×40 mL). The combined EtOAc extracts were washed with water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/CH2Cl2 (1:9) to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.67-1.76 (m, 2 H), 1.84-1.91 (m, 2 H), 1.99-2.17 (m, 4 H), 3.95-3.99 (m, 4 H), 4.18-4.27 (m, 1 H). MS (ES+): m/z=334.96 (100) [MH+]. HPLC: tR=3.26 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCC1=Cc1ccc(F)cc1
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: O=C1NCCC1Cc1ccc(F)cc1
Yield: 99.5 %

Procedure:
This example describes the preparation of I where n=1 and R1=p-fluorophenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-fluorobenzylidene)-2-pyrrolidinone (250 mg, 1.3 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-p-fluorobenzyl-2-pyrrolidinone (250 mg, 100%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak OD, 95% heptane, 4.9% isopropanol, 0.05% trifluoroacetic acid, 0.05% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 88%. 19F NMR δ −117.39; 13C NMR δ 26.92, 35.90, 40.44, 42.88, 115.44 (d, J=21 Hz), 130.58, 135.21, 161.77 (d, J=241 Hz), 179.72; 1H NMR: δ 1.83 (m, 1H), 2.15 (m, 1H), 2.66 (m, 2H), 3.11-3.32 (m. 3H), 6.47 (br s, 1H), 7.00 (m, 2H), 7.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Yield: 25.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.5 g, 14.6 mmol) and SOCl2 (2.7 mL, 36.4 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.1 mL, 29.1 mmol) and CHCl2 (75 mL). The product chromatographed in CH2Cl2 is to provide 1.05 g of a yellow orange solid (26%). 1H NMR (CDCl3) δ: 8.54 (d, J=8.1 Hz, 1H); 8.30 (br s, 1H); 7.41 (dd, J=1.5, 8.0 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.10 (t, J=8.1 Hz, 1H); 7.09 (dt, J=1.6, 7.8 Hz, 1H); 6.78 (dd, J=0.4, 7.9 Hz, 1H); 6.63 (dd, J=0.9, 8.2 Hz, 1H); 4.69 (br s, 2H). MS (ES): m/z 303.0 (M+22), 281.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)[CH:3]=1.O.[CH3:16][NH:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][N:17]([CH3:18])[CH3:16])[CH:3]=1
Reactant: CNC
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1sccc1-c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (20 mg, 0.1 mmol) in dichloromethane (3 mL) was added dimethylamine water solution (40%, 0.6 mL) and sodium triacetoxyborohydride (42 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 16 hours, then washed with NaHCO3 solution and water and concentrated. The resulting residue was purified by preparative TLC to yield [3-(4-Chloro-pyridin-2-yl)-thiophen-2-ylmethyl]-dimethyl-amine.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:10][CH2:11][OH:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:9][C:4]1[C:3]([CH2:10][CH2:11][OH:12])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3,4-difluoro-2-(2-hydroxyethyl)phenol (460 mg, 2.64 mmol) in Acetone (10 mL) was added K2CO3 (730 mg, 5.28 mmol) followed by (bromomethyl)benzene (0.471 mL, 3.96 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(6-(benzyloxy)-2,3-difluorophenyl)ethanol (580 mg, 2.195 mmol, 83% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 6.99 (q, J=9.1 Hz, 1H), 6.67-6.59 (m, 1H), 5.09 (s, 2H), 3.86 (q, J=6.4 Hz, 2H), 3.05 (td, J=6.5, 1.7 Hz, 2H).