Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]3O[C:18](=O)[CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2]C>CCCCCCC>[CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)=[CH2:2]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CC(=O)O3)CC2)CC1
Solvent: CCCCCCC
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC)CC2)CC1
Temperature: 170 °C

Procedure:
4-(trans-4-(trans-4-Propylcyclohexyl)cyclohexyl)-2-oxetanone (1 g, 3.1 mmol) obtained in Example 2 was placed in a reactor, the interior of which was then sufficiently replaced by nitrogen. The reactor was heated, and after heating to 170° C. for 3 hours, it was cooled to room temperature. The resulting solid was dissolved in heptane and purified with silica gel chromatography to provide trans-1-ethenyl-4-(trans-4-propyl-cyclohexyl)cyclohexane (0.83 g, 30 mmol, yield: 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:23][C@H:22]([NH:24][C:25]([C@:27]34[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:28]3[C@@H:29]3[C@@:42]([CH3:45])([CH2:43][CH2:44]4)[C@@:41]4([CH3:46])[C@@H:32]([C@:33]5([CH3:50])[C@@H:38]([CH2:39][CH2:40]4)[C:37]([CH3:48])([CH3:47])[C@@H:36]([OH:49])[CH2:35][CH2:34]5)[CH2:31][CH2:30]3)=[O:26])[C:21]2([CH3:58])[CH3:57])=[O:19])[CH2:14][CH2:13]1)[CH3:11]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:23][C@H:22]([NH:24][C:25]([C@:27]34[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:28]3[C@@H:29]3[C@@:42]([CH3:45])([CH2:43][CH2:44]4)[C@@:41]4([CH3:46])[C@@H:32]([C@:33]5([CH3:50])[C@@H:38]([CH2:39][CH2:40]4)[C:37]([CH3:47])([CH3:48])[C@@H:36]([O:49][C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH2:35][CH2:34]5)[CH2:31][CH2:30]3)=[O:26])[C:21]2([CH3:57])[CH3:58])=[O:19])[CH2:14][CH2:13]1)[CH3:11]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 60.6 %

Procedure:
2,2-Dimethylsuccinic anhydride (238 mg) was added to a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 67, 125 mg) and DMAP (45 mg) in dry pyridine (10 mL) at room temperature. After addition, the reaction mixture was refluxed for 14 hours. After completion of the reaction (monitored by TLC), it was diluted with EtOAc, the organic layer was washed with aqueous 1N HCl, then washed with water and brine, and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford 90 mg of title compound (60.8% yield) as an off white solid with 81.67% HPLC purity. 1H-NMR (300 MHz, CDCl3): δ 5.92 (d, J=7.8 Hz, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.44 (m, 1H), 4.19-4.09 (m, 1H), 3.90 (m, 2H), 3.7 (m, 2H), 3.15-3.04 (m, 1H), 2.87-2.82 (m, 6H), 2.60 (m, 3H), 2.5-2.3 (m, 3H), 2.00-1.91 (m, 3H), 1.75-1.10 (m, 36H), 0.947, 0.914, 0.900 (s, 18H); Mass: [M+1]+ 806 (100%); IR (KBr, cm−1): 3394, 2957, 2873, 1724, 1623, 1455, 1374, 1367, 1244, 1188, 1146, 980, 883, 765; M.R: 63.8° C.-122.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:20][C:21]1[C:22]([CH2:27]Cl)=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C>[CH3:20][C:21]1[C:22]([CH2:27][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:4][C:5]=3[N:9]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccnc1CCl
Reactant: CN1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccnc1CSc1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Yield: 21.5 %

Procedure:
The title compound (0.6 g, 22%) was prepared by the general procedure using 6-fluoro-5-(4-methylpiperazin-1-yl)-2-mercapto-1H-benzimidazole (2.0 g, 7.5 mmol) (obtained in preparation 4), 3-methyl-2-chloromethylpyridine hydrochloride (1.0 g, 7.5 mmol), sodium hydroxide (0.36 g, 9.0 mmol) and ethanol (15 mL). IR (Neat) 3150, 1429 cm-1 ; 1H NMR (CDCl3) δ 2.42 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.90 (m, 4H, N(CH2)2), 3.20 (m, 4H, N(CH2)2), 4.38 (s, 2H, SCH2), 7.12 (d, J=7.6 Hz, 1H), 7.20-7.26 (m, 2H), 7.58 (d, J=7.4 Hz, 1H), 8.46 (d, J=4.6 Hz, 1H); Mass (m/z) 371 (M+.).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27]>C1COCC1>[F:11][CH2:10][CH2:9][O:8][C:7]1[C:2]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FCCOc1cccnc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ncccc2OCCF)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 28 (7.3 mmol) in THF was added 1.6 N butyllithium/hexane solution (7 ml) at −78° C. under N2 atmosphere. The solution was stirred at −78° C. for 1 hour and a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1 g, 3.6 mmol) in THF was added. The solution was maintained at −78° C. for 4 hour, and then quenched with sat. aqueous NH4Cl and allowed to warm to rt with stirring. The organic layer was separated and then the aqueous layer was extracted with ethyl acetate. The combine extract was washed with water, dried over Na2SO4, filtered, concentrated, and the residue chromatographed on silica eluted with an ethyl acetate-hexane (1:4, v/v) and the aimed product was obtained. The yield was 40%. NMR (CDCl3): δ 1.47 (s, 9H), 1.62-1.70 (m, 4H), 2.83 (s, 2H), 3.64-3.73 (m, 1H), 4.17 (br, 2H), 4.25-4.36 (m, 2H), 4.68-4.87 (m, 2H), 7.23-7.26 (m, 1H), 7.38-7.40 (m, 1H), 8.25-8.30 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][NH:10]3)[CH2:3][CH2:2]1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[CH:1]1([CH2:4][O:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@@H:18]2[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([F:15])[CH2:17]2)[CH2:2][CH2:3]1
Reactant: c1nc(OCC2CC2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(OCC4CC4)ncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 144 h
Yield: 57.8 %

Procedure:
6-Cyclopropylmethoxy-9H-purine (0.50 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 40 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 6 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.392 g of 6-cyclopropylmethoxy-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (58%): mp 100° C.; TLC Rf 0.90 (silica gel, MeCN:15N NH4OH:H2O/ 85:5:10); [α]D20 -18.8 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 251 (12.5); at pH 13, 149.5 (12.1); 1H NMR (400 MHz, DMSO-d6) δ8.59 and 8.50 (2s, 2H, H2 and H8), 6.46 (dd, 1H, H1', J=9.1 Hz, J=5.7 Hz), 5.44 (dd, 1H, H3', J=53.5 Hz, J=4.4 Hz), 5.23 (t, 1H, OH5', J=5.6 Hz), 4.37 (d, 2H, OCH2, J=7.4 Hz), 4.18-4.29 (m, 1H, H4'), 3.57-3.60 (m, 2H, H5' and H5"), 2.92-3.10 and 2.65-2.75 (2m, 2H, H2' and H2"), and 1.25-1.35, 0.55-0.60, and 0.36-0.40 (3m, 5H, cyclopropyl); MS (ci)309 (M+1), 289 (M-F), 191 (MH2 --C5H8FO2).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])=[CH:3][CH:4]=1
Reactant: OCc1ccc(S)cc1
Reactant: N#Cc1cncc(Br)c1
Product: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Yield: 49.5 %

Procedure:
Using the method of Preparation 153 using (4-mercaptophenyl)methanol (4.42 g, 31.5 mmol) and 5-bromonicotinonitrile (5.49 g, 30.0 mmol) affords the title compound (3.60 g, 50%): 1H NMR (CDCl3) δ 1.92 (t, J=5.9 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 7.48 (q, J=8.2 Hz, 4H), 7.58 (t, J=2.0 Hz, 1H), 8.61 (dd, J=2.0, 3.1 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(CCCCCBr)c1c[nH]c2ccccc12

Procedure:
Using indole (5.00 g) and 6-bromohexanoyl chloride (9.95 ml) according to the same method as that of Reference Example 1, the title compound (9.65 g) was obtained as colorless crystals having a melting point of 150 to 151° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[CH:23]=2)=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.O=S(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[C:23]=2[C:6]([C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)O)cc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(C#N)c2)cc1
Yield: 107.5 %

Procedure:
1.8 g of the title compound was prepared from 3.9 g (3.9 mmol) of 3-cyano-4-methoxybenzoic acid (converted to the acid chloride with 30 mL of SOCl2 and three drops of DMF), 6 g (22 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 14.7 g (110 mmol) of AlCl3 in a manner similar to that in Preparation 4.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4,4-diphenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield. mp 198°-199°. FDMS m/e=426(M + of free base). α[D]589 =-17.80 (c=0.66, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH2:10][CH:11]1[O:13][CH2:12]1.O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][CH:11]([OH:13])[CH2:10][CH3:9]
Reactant: CCC1CO1
Reactant: Oc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(Cl)c1

Procedure:
is obtained analogously to Example H1 by using 51.4 g of 3-chlorophenol, 28.8 g of α-butylene oxide and 1.0 g of lithium hydroxide monohydrate in a yield of 71.4 g in the form of an oil; b.p. 83°-84° C./0.04 torr.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=[O:4].C1(=O)OCCCCC1>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>[CH3:1][C@H:2]1[O:9][C:7](=[O:8])[C@@H:6]([CH3:10])[O:5][C:3]1=[O:4]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: O=C1CCCCCO1
Agent: [Sn+2]
Product: C[C@H]1OC(=O)[C@@H](C)OC1=O
Temperature: 150 °C

Procedure:
An amorphous, non-crystallizable copolymer of 80 mol. % L-lactide and 20 mol. % D-lactide was prepared by ring-opening polymerisation in the melt, in the presence of 0.1% by weight tin octoate as catalyst. To this polymer was added an amount of 20% by weight of ε-caprolactone, whereafter, under nitrogen and with continuous mechanical stirring, the mixture was heated to 150° C. To the homogeneous mixture, again 0.1% by weight tin octoate as catalyst was added, whereafter the polymerisation was completed.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:19]([C:23]1[N:24]=[C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34](O)=[CH:33][C:31]=3[CH:32]=2)[S:26][CH:27]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:19]([C:23]1[N:24]=[C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([O:1][CH2:2][C:3]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=4[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:33][C:31]=3[CH:32]=2)[S:26][CH:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(C)Oc1c(CO)cccc1OC
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)cccc1OC
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of ethyl 2-(2-hydroxymethyl-6-methoxyphenoxy)propionate (1.97 g), 2-(4-tert-butylthiazol-2-yl)-5-hydroxybenzofuran (1.83 g), and triphenylphosphine (2.83 g) in tetrahydrofuran (20 ml) was added a solution of diethyl azodicarboxylate (1.67 g) in tetrahydrofuran (2 ml) under ice-cooling. The mixture was stirred at the same temperature for an hour and at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was subjected to a column of silica gel (250 ml) eluting with a mixed solvent of n-hexane and ethyl acetate (7:1) to give ethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionate (2.31 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccccc1-c1ccc(C#N)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
A mixture of ethyl 2-(4′-cyanobiphenyl-2-ylthio)-2-methylpropanoate (93 mg, 0.286 mmol) and aqueous sodium hydroxide solution (1 M, 2 mL) in methanol (4 mL) was stirred at 60° C. for 12 hours. The reaction mixture was concentrated to remove methanol, acidified and filtered to obtain a white powder, which was purified by chromatography to yield 2-(4′-cyanobiphenyl-2-ylthio)-2-methylpropanoic acid (38.1 mg, 45%). By-product 2-(4′-carbamoylbiphenyl)-2-ylthio)-2-methylpropanoic acid (38.4 g) was also obtained. 1H NMR (400 MHz, DMSO-d6, 25° C.) 7.67-7.72 (m, 3H), 7.48-7.54 (m, 3H), 7.37-7.43 (m, 2H), 1.33 (s, 6H). MS (m/z) 296.16 (M-1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.N1C=CC=CC=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)#[N:22]>ClCCl.C1COCC1.CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
4-Chloro-3-(pyridin-2-yl)aniline (687 mg, 3.36 mmol) was dissolved in dichloromethane (8.0 ml) and THF (8.0 ml), treated with pyridine (0.33 ml, 4.0 mmol), and cooled to 0° C. 4-Cyanobenzoyl chloride (612 mg, 3.7 mmol) was added and the reaction was stirred for 1.0 hour. The reaction was diluted with dichloromethane and methanol was added to dissolve all solids. The solution was washed with water once, brine once, dried with MgSO4, and evaporated to an orange solid which was purified by silica gel flash column chromatography (50% ethyl acetate/50% hexanes) to afford 908 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide as a yellow solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (500 mg, 1.5 mmol) was slurried in ethanol (75 ml) and heated until just dissolved. The solution was cooled in an ice bath, and saturated with HCl gas. The solution was heated briefly to 70° C. to dissolve precipitated solids, cooled in an ice bath, and resaturated with HCl gas. The solution was then stored at 0° C. for 18 hours. The solution was saturated again with HCl gas, heated to 70° C. until all solids dissolved, cooled to 0° C., resaturated with HCl gas, and stored at 0° C. for 18 hours. Finally, nitrogen gas was bubbled through the solution for 1.0 hour, and the solution was evaporated to dryness. The residue was dissolved in methanol, treated with MP-carbonate (2.57 g) and stirred 30 min. The solution was filtered to afford a neutral, methanolic solution of ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate, which was diluted with enough methanol to make a 0.075 M solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2([O:15][C:14]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=3[CH:12]=[CH:11]2)[N:9]([CH2:23][CH2:24][OH:25])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:26])[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]([CH2:23][CH2:24][O:25][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:10]21[CH:11]=[CH:12][C:13]1[C:14](=[CH:16][CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[O:15]2
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)c2ccccc2N(CCO)C12C=Cc1cc([N+](=O)[O-])ccc1O2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)c2ccccc2N(CCOC(=O)CCC(=O)O)C12C=Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
About 2 g of 1-(2-Hydroxyethyl)-3,3-dimethylindolino-6′-nitrobenzopyrylospiran (TCI America), about 0.44 ml of triethylamine, and about 0.69 g of 4-(dimethylamino)pyridine were dissolved in about 30 ml of dichloromethane. After addition of about 0.59 g of succinic anhydride, the solution was stirred under Ar at room temperature for about 19 hours. The mixture was washed with 5% aqueous hydrochloric acid, aqueous sodium bicarbonate, and water, then dried over magnesium sulfate. After the solvent was distilled off, the concentrated solution was added dropwise to hexane under stirring. The resulting solid was collected by filtration to yield 4-(2-(3′,3′-dimethyl-6-nitrospiro[chromene-2,2′-indoline]-1′-yl)ethoxy)-4-oxobutanoic acid.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[N:31]=[C:32]([CH2:35]O)[S:33][CH:34]=1>C1(C)C=CC=CC=1>[N:15]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([CH3:29])[N:31]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(CO)n1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1csc(CN=[N+]=[N-])n1
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (DPPA) (1.2 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of (4-methylthiazol-2-yl)methanol (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded 2-(azidomethyl)-4-methylthiazole.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:49]1([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][C:53]=2[N:58]2[CH2:62][CH2:61][NH:60][C:59]2=[O:63])[CH2:51][CH2:50]1.Cl[C:65]1[N:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[CH:68]=[CH:67][N:66]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH:49]1([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][C:53]=2[N:58]2[CH2:62][CH2:61][N:60]([C:65]3[N:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[CH:68]=[CH:67][N:66]=3)[C:59]2=[O:63])[CH2:51][CH2:50]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1N(c2nccc(C(F)(F)F)n2)CCN1c1cnccc1C1CC1
Temperature: 110 °C
Yield: 34.9 %

Procedure:
Xantphos (23 mg, 0.049 mmol) and Pd2(dba)3 (22.5 mg, 0.024 mmol) were added to a solution of cesium carbonate (400 mg, 1.23 mmol) in toluene (5 mL) previously purged with nitrogen (20 minutes). The reaction mixture was purged with argon for 10 minutes, followed by the addition of, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (0.06 ml, 0.54 mmol). The reaction mixture was heated in seal tube at 110° C. for 16 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was cooled, filtered and the filtrate partitioned between ethyl acetate and water. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 60 mg of the product (35% yield).