Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:30](Cl)(=[O:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][C:30](=[O:32])[CH3:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (20 mg, 0.05 mmol) in DCM (0.5 mL) were added acetyl chloride (7 μL, 0.10 mmol) and NEt3 (14 μL, 0.10 mmol). After stirring for 1 h, the solvent was evaporated and the residue was purified by preparative HPLC to provide 11.3 mg (56%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide 21. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5; found 417.2 [M+H]+, tR=3.56 min. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.83 (d, J=8.6 Hz, 1H), 5.36-5.21 (m, 1H), 4.79 (hept, J=6.0 Hz, 1H), 3.16 (dt, J=17.9, 6.0 Hz, 1H), 3.03 (dt, J=18.2, 6.3 Hz, 1H), 2.10-1.99 (m, 4H), 1.97-1.79 (m, 3H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)CNc1ccnc(Cl)n1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(CBr)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (2.0 g, 10.0 mmoles) and 1,4-bis-bromomethyl-benzene (4.0 g, 15.0 mmoles) are dissolved in 50 ml of DMF and NaH (0.8 g, 21.0 mmoles, 60% oil suspenstion) is added at 0° C. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 0.9 g of desired (4-bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 24% yield.
Reaction SMILES: [C:1]([OH:9])(=[O:8])C1C=CC=CC=1.Br[C:11]1[CH:12]=[CH:13][C:14]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:16]=1>>[C:25]([C:14]1[CH:13]=[CH:12][C:11]([C:1]([OH:9])=[O:8])=[CH:16][C:15]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: O=C(O)c1ccccc1
Product: Cc1ccc(Oc2cc(C(=O)O)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 4-tert-butyl-3-(4′-trifluoromethyl)phenoxy] benzoic acid (Compound P), 1.02 g (3.2 mmol) of 5-bromo-2-tert-butyl-1-[(4′-methyl)phenoxy]benzene (Compound J) was converted into the title compound using 4.7 mL (8.0 mmol) of tert-butyllithium solution (1.7M in pentane) and 10 mL of tetrahydrofuran. Purification by flash chromatography (silica, 3% methanol in chloroform) gave the title compound as a creme solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]2=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)cc1)N1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-chlorophenyl)-ethylamine (117 mg (0.75 mmol), 2-bromomethyl-benzoic acid methyl ester (172 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to ethyl acetate afforded 38 mg of 2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one, as the racemic mixture. Chromatography (HPLC) of this material through ChrialCel OD (250×20 mm i.d., 10 μm) using 5% isopropanol in hexanes afforded 11.6 mg of R-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one and 8.3 mg of S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one. GC/MS for S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one gave: m/z (rel.int.) 274 (M+, 9), 272 (M+, 56), 258 (26), 256 (57), 160 (20), 138 (32), 119 (100), 103 (50), 91 (65), and 77 (61).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH2:20])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(Cl)Cl.[N:25]([CH2:28][CH2:29][O:30][N:31]=[C:32]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)[C:33](O)=[O:34])=[N+:26]=[N-:27].ON1C2C=CC=CC=2N=N1.Cl>O.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:33](=[O:34])[C:32]([C:36]4[N:37]=[C:38]([NH:41][C:42]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[S:39][CH:40]=4)=[N:31][O:30][CH2:29][CH2:28][N:25]=[N+:26]=[N-:27])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.652 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-amino-ceph-3-eme-4-carboxylic acid, 6.5 ml of methylene chloride and 0.56 ml of triethylamine was stirred at room temperature for 15 minutes and then 1.29 g of 1-hydroxy-1H-benzotriazole 2-(2-azidoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate were added thereto. The mixture was stirred at room temperature for 20 hours and then 10 ml of water and 3 ml of 2 N hydrochloric acid were added thereto. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken up in 5 ml of ethyl acetate and 10 ml of ether were added thereto. The mixture was stirred for 30 minutes at room temperature and was vacuum filtered to obtain 1.416 g of raw syn isomer of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: I[C:2]1[C:3]([CH:13]=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:43]=[CH:42][CH:41]=[CH:40][C:23]=1[O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:22]1[CH:43]=[CH:42][CH:41]=[CH:40][C:23]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([CH:13]=[O:14])=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3F)cc2)OC1(C)C
Reactant: O=Cc1nn(C2CCCCO2)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)cc1-c1ccc(Oc2ccccc2F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of 4-iodo-1-(oxan-2-yl)-1H-pyrazole-3-carbaldehyde (227 mg, 0.74 mmol, 1.00 equiv), Pd(dppf)Cl2 (54 mg, 0.07 mmol, 0.10 equiv), potassium carbonate (304 mg, 2.20 mmol, 2.97 equiv) and 2-[4-(2-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280 mg, 0.89 mmol, 1.20 equiv) in 1,4-dioxane (20 mL) and water (2 mL) was stirred under nitrogen at 100° C. overnight. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified on a silica gel column eluted with 1-9% ethyl acetate in petroleum ether to give 160 mg (59%) of 4-(4-(2-fluorophenoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1H), 7.91 (s, 1H), 7.60 (d, J=2.1 Hz, 2H), 7.57-7.43 (m, 1H), 7.43-7.40 (m, 3H), 7.03 (d, J=2.1 Hz, 2H), 6.14-6.10 (m, 1H), 4.00-3.99 (m, 1H), 3.68-3.66 (m, 1H), 2.30-2.28 (m, 1H), 1.98-1.93 (m, 2H), 1.56-1.55 (m, 2H), 1.19-1.17 (m, 1H) ppm. LCMS (method D, ESI): RT=1.78 min, m/z=367.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:21])[CH3:20])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:21][N:19]([CH3:20])[C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])=[CH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:66]([C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:56]=3)=[O:67])=[CH:14][CH:13]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Reaction time: 3 h

Procedure:
A solution containing methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was treated with 2-naphthoic acid (0.062 g, 0.36 mmol). The reaction mixture was stirred for 3 hours before diluting with water. The thus quenched reaction mixture was extracted with EtOAc and the combined organic extracts was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the crude product methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.O>C(O)C>[CH:17]1([NH:22][C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=3[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CC(=O)c2cc(C#N)c(NC3CCCC3)nc2C1
Yield: 48.3 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.25 g, 1.06 mmol), cyclopentylamine (0.136 g, 1.6 mmol) and triethylamine (0.154 ml, 0.11 g, 1.1 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:1) to give the title compound (0.145 g, 48%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.FC(F)(F)C(O)=O.[Cl:37][C:38]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:39]=1[CH2:40][C:41]([N:43]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH2:44][CH3:45])=[O:42]>>[Cl:37][C:38]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:39]=1[CH2:40][C:41]([N:43]([CH:46]1[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:48][CH2:47]1)[CH2:44][CH3:45])=[O:42]
Reactant: CCN(C(=O)Cc1ccc(F)cc1Cl)C1CCNCC1
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Cc1ccc(F)cc1Cl)C1CCN(C[C@H]2CN([C@H](CC3CCC3)C(=O)O)C[C@@H]2c2ccccc2)CC1
Yield: 14.7 %

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester (25 mg, 0.07 mmol, Aldehyde 1) and 4-(N-((2-chloro-4-fluorobenzyl)carbonyl)-N-ethylamino)piperidine trifluoroacetate (41 mg, 0.1 mmol, from Example 14 , Step A) according to the method described in Example 14 , Step B to give 6.0 mg (15%) of the title compound. ESI-MS: 584.3 (M+H); HPLC A: 2.70 min.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]>CN(C)C(=O)C>[Cl:9][C:10]1([C:15]([O:17][CH3:1])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)C1(Cl)CC1(Cl)Cl
Reaction time: 20 h

Procedure:
Potassium carbonate (4.14 grams) and methyl iodide (3.74 ml) were added to a solution of 1,2,2-trichlorocyclopropane carboxylic acid (5.68 grams) and N,N-dimethylacetamide (50 ml). The reaction mixture was stirred for approximately 20 hours and then filtered. Ethyl ether (250 ml) was added to the filtrate and the resultant mixture was washed, dried, and evaporated in vacuo to the desired product, methyl 1,2,2-trichlorocyclopropane carboxylate. Structure of the product was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][N:27]=[CH:26]1.C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO.CC(C)=O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:33][CH2:32][CH2:31][CH2:30][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH2:18][CH2:17]1
Reactant: NCCCn1ccnc1
Reactant: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)Cn1c(CN2CCC(NCCCn3ccnc3)CC2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 72.9 %

Procedure:
To the mixture of 100 mg (0.30 mmoles) of 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 60 mg (0.48 mmoles) of 3-Imidazol-1-yl-propylamine and 0.15 ml (1.1 mmoles) of triethylamine in 5 ml of CH2Cl2, 58 mg (1.1 mmoles) of MgSO4 is added at ambient temperature. The mixture is stirred for 15.5 hours at ambient temperature. The reaction mixture is filterlated to remove MgSO4 and concentrated under reduced pressure to give crude imine. To a solution of crude imine in 5 ml of MeOH, 13 mg (0.33 mmoles) of NaBH4 is added at −10-−20° C., and the reaction mixture is stirred at 0° C. for 4.5 hours. After addition of 5 ml of acetone, the mixture is concentrated, diluted with H2O, and then extracted with CH2Cl2. The combined extrats are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 95 mg of desired 7-(2,2-dimethyl-propyl)-6-[4-(3-imidazol-1-yl-propylamino)-piperidin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 73% yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[Cl:24])[CH2:12][CH2:11]1)(=O)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:24][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:17]=1[O:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:7][CH3:8])[CH2:11][CH2:12]1)[NH2:21]
Reactant: CC(=O)N1CCC(Oc2ccc(N)cc2Cl)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccc(N)cc2Cl)CC1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a suspension of lithium aluminum hydride (230 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of 4-(1-acetylpiperidin-4-yloxy)-3-chloroaniline obtained in reference example 10 in tetrahydrofuran (10 ml) with stirring under ice-cooling in a nitrogen atmosphere, and the resulting mixture was refluxed for 3.5 hours. After refluxing, to the reaction mixture was furthermore added lithium aluminum hydride (115 mg), and the resulting mixture was refluxed for a further 2 hours. After cooling to room temperature, to the reaction mixture was added sodium sulfate decahydrate, and the resulting mixture was furthermore stirred at room temperature overnight. After removing insoluble materials by filtration, the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (3:1˜1:2) as the eluent to afford the title compound (448 mg, yield: 58%) as a brown oil.
Reaction SMILES: Br[CH2:2][CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCCCCCCC>CO.CC(O)C>[CH2:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(Br)CBr
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CO
Solvent: CC(C)O
Product: C=CCCCCCCCC

Procedure:
Solutions were prepared by dissolving all of the following in a total volume of 5 mL methanol and 2-propanol, respectively: (a) 60.0 mg 1,2-dibromodecane, 10.8 mg of benzophenone and 12.6 mg of dodecane; (b) 65.2 mg 1,2-dibromodecane, 11.2 mg benzophenone and 11.2 mg dodecane. Two 2mL-aliquot of each solution were placed in quartz cells (7×7 mm2) and deaerated by bubbling oxygen-free nitrogen for 15 minutes. Samples were then irradiated at 350 nm using a photoreactor equipped with two RPR-350 lamps. Samples were rotated with a "merry-go-round" (to ensure that all samples received the same irradiation dose) and irradiated for 1 hour (methanol) or 40 minutes (2-propanol). A valerophenone solution (prepared as described above) was used as a relative actinometer. Product (i.e. 1-decene) quantification and quantum yields were carried out as described above. Results are summarized in the table below. No 1-decene was formed in the absence of benzophenone.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=[O:3].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH3:10])[O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: COCCOCCOCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OC(Cl)C(C)C

Procedure:
In a manner similar to the method described in Example 3, 1-chloro-2-methylpropyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloro-2-methylpropyl 2-(2-(2-methoxyethoxy)-ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 15-methyl-12-oxo-2,5,8,11,13-pentaoxahexadecan-14-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C43H52Cl2F2N3O10: [(M+H)+]: 878, found: 878.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH2:16])=[C:10]([CH3:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](O)(=[O:22])[C:20]#[CH:21].CCN(C(C)C)C(C)C.CCCP(=O)=O.CN(C=O)C>C(Cl)Cl>[CH3:14][C:12]1[C:11]([CH2:15][NH:16][C:19](=[O:22])[C:20]#[CH:21])=[C:10]([CH3:17])[N:9]=[C:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=1
Reactant: C#CC(=O)O
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NCc1c(C)cc(NC(=O)OC(C)(C)C)nc1C
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a solution of (5-aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (4.50 g, 17.90 mmol), propiolic acid (0.918 ml, 14.92 mmol), DIPEA (7.82 ml, 44.8 mmol) in DCM (140 ml) at 23° C. was added dropwise over 5 min 50% propylphosphonic anhydride in DMF (12.5 ml, 21.41 mmol). The reaction was stirred at 23° C. for 1 day. The reaction was quenched by addition of brine, and the phases were separated. The aqueous phase was further extracted with DCM, and the combined organic phase was dried over Na2SO4, filtered, and evaporated to provide the crude product, which was purified by flash column chromatography (silica gel 0.040-0.063 mm, 160 g, flow rate 60 ml/min, detection at 220 nm, MeOH in DCM 0->1% over 10 min, then 1->5% over 20 min) to yield the title compound. HPLC (Method G) Rt=1.333 min; MS (Method F) [M+H]+=304.31.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]([O:18][CH:13]([CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CN=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
3-Azido-2-hydroxypropyl 4-methylbenzenesulfonate 14 (1.83 g, 6.70 mmol) was dissolved in CH2Cl2 (15 mL) and treated with TEA (1.4 mL, 10.00 mmol), a catalytic amount of DMAP and acetic anhydride (0.95 mL, 10.00 mmol) at room temperature. After stirring for 1 hr, silica was added to the reaction mixture, the solvent was evaporated and the residue was purified on silica gel using 50% EtOAc/hexanes as the eluent to afford 2.07 g of 15 (98.8% yield) as a thick, clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 5.02-5.07 (m, 1H), 4.09-4.21 (m, 2H), 3.43-3.53 (m, 2H), 2.46 (s, 3H), 2.05 (s, 3H). Mass Spec (lo-res): Calc'd for C12H15N3O5S: 313.07; found: 314.1 (M+H+).