Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(Cl)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Yield: 51 %

Procedure:
[step 2] Using 8-chloro-3-iodo-2-isopropylimidazo[1,2-a]pyridine (393 mg, 1.23 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{8-[(8-chloro2-isopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (254 mg, 51%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Clc1ccccc1C1CCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccccc2Cl)cc1

Procedure:
The title compound, white solid, m.p. 149° C. and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[Br:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.CN(C=O)C>C1COCC1>[Br:42][C:43]1[CH:44]=[N:45][C:46]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:47][CH:48]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissoved in THF (8 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Bromo-2-chloro-pyrimidine (37 mg) was added and the mixture was heated to 60° C. for 120 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silica gel with EtOAc/Hex=1:1 to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (55.4 mg). tR=5.30 min, (LC); [M+H]+=710.35 (ES+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:30]([C:32]1[C:36]([CH:37]=O)=[CH:35][NH:34][N:33]=1)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:28]=[CH:29][C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:37][C:36]3[C:32]([CH2:30][CH3:31])=[N:33][NH:34][CH:35]=3)[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CCc1n[nH]cc1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1n[nH]cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 395 mg, 1.0 mmol) and 3-ethyl-1H-pyrazole-4-carbaldehyde (149 mg, 1.2 mmol) were stirred at ambient temperature in dichloromethane (10 ml) for 1 hour. Sodium triacetoxyborohydride (297 mg, 1.4 mmol) was added and the mixture stiffed at ambient temperature for 24 hours. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the product as a white foam. This was purified by chromatography on silica eluting with 10% methanol in dichloromethane. The residue was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was added and the mixture stirred for 3 hours at ambient temperature. The resulting solution was absorbed onto an SCX-2 column which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the title compound (232 mg, 75%). NMR Spectrum: (DMSO d6) δ 1.18 (t, 3H), 1.65 (m, 2H), 1.77 (m, 2H), 2.00 (m, 2H), 2.57 (m, 3H), 2.95 (m, 2H), 3.34 (s, 2H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.29 (br s, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H), 12.39 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:34][Si:5]([CH3:35])([CH2:4][CH2:3][CH2:2][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1)[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12
Reactant: c1nc[nH]n1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCn1cncn1
Yield: 61 %

Procedure:
A solution of Compound 11 (50 mg), 1,2,4-triazole (31 mg) and NaHCO3 (15 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 61% yield (30 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33]N1C(=O)CCC1=O.O>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[Cl:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2Cl)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 93.3 %

Procedure:
To a solution of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (1.0 g) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (292 mg) at ambient temperature, and the mixture was allowed to stand for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-chloropyrrole (1.0 g) as an oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CC(=O)N1CC(=O)Nc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)N(CC2OCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 15 mL of an N,N-dimethylformamide solution containing 957 mg of 4-acetyl-3,4-dihydro-2-oxo-1H-quinoxaline, 668 mg of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.6 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90° C. for 6 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; chloroform] to obtain 1.30 g of a brown oily substance, 4-acetyl-1-(1,3-dioxolan-2-ylmethyl)-2-oxo-3,4-dihydro-1H-quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1C1OCCO1
Yield: 116.6 %

Procedure:
2-Chloro-6-fluorobenzaldehyde (100 g), ethylene glycol (192 g) and p-toluenesulphonic acid (17 g) were dissolved in toluene and heated under reflux for four days using a Dean and Stark adapter to collect the water. After cooling the mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-(2-chloro-6-fluorophenyl)-1,3-dioxolane (149 g) as an orange oil, NMR (CDCl3) 4.05(m,2H), 4.3(m,2H), 6.35(s,1H), 7.2(m,3H).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:29][CH2:30][CH2:31][O:32][CH2:33][C@H:34]([OH:39])[C:35](OC)=[O:36])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Si:12]([O:29][CH2:30][CH2:31][O:32][CH2:33][C@H:34]([OH:39])[C:35]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:36])([C:25]([CH3:28])([CH3:26])[CH3:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Trimethylaluminium (3.73 mL, 7.45 mmol) was added to pyridin-2-amine (0.701 g, 7.45 mmol) in toluene (6 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (1.5 g, 3.73 mmol) (Intermediate AB3) in toluene (6 ml) was added and the reaction was allowed to warm to room temperature and then heated to 110 for 5 hours in a microwave. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 ml), then dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.085 g, 62.7%). 1H NMR: (400 MHz, CDCl3) δ 1.05 (9H, t), 3.60-3.66 (2H, m), 3.67 (1H, d), 3.82-3.84 (2H d, m), 3.80-3.85 (2H, m), 4.33-4.35 (1H, m), 7.03-7.06 (1H, m), 7.35-7.68 (10H, m), 7.70 (1H, d), 8.22 (1H, d), 8.29-8.30 (1H, m),9.15 (1H, s); m/z (ES+) (M+H)+=465.42; HPLC tR=3.13 min.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[C:12]#[N:13].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[C:47]([O:51][C:52]([NH:54][C@@H:55]([CH2:59][CH3:60])[C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52](=[O:53])[NH:54][C@H:55]([C:56](=[O:57])[NH:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[C:11]([C:12]#[N:13])[C:10]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:59][CH3:60])([CH3:48])([CH3:49])[CH3:50]
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(C#N)c1Nc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.55 mL, 3.96 mmol) was added to a stirred mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (0.30 g, 1.32 mmol), (S)-(2-tert-butoxycarbonylamino)butyric acid (0.30 g, 1.45 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.28 g, 1.45 mmol) and HOAt (0.20 g, 1.45 mmol) in DCM at 0° C. under nitrogen. The resultant mixture was stirred at 0° C. for 5 minutes then 20° C. for 16 h. The reaction mixture was re-cooled to 0° C. and (S)-2-tert-butoxycarbonylaminobutyric acid (0.30 g, 1.45 mmol), N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide hydrochloride (0.28 g, 1.45 mmol), HOAt (0.20 g, 1.45 mmol) and triethylamine (0.55 mL, 3.96 mmol) added sequentially, and the resultant mixture stirred at 20° C. for 24 h. The mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (3×20 mL). The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound as an off white foam (0.64 g). LCMS (method H): Rt 2.93 min, [M+H]+ 413.
Reaction SMILES: Cl[C:2]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]1[F:5].NCCN>[Ni].C(O)C>[F:5][CH:3]1[CH2:4][CH:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C1(Cl)CC1F
Agent: [Ni]
Solvent: CCO
Solvent: NCCN
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 1-chloro-2-fluoro-1-cyclopropanecarboxylate (cis:trans=1.4:1), 0.5 ml of Raney nickel and 5 ml of ethanol were fed thereinto. Then 0.18 mg of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (10 kgf/cm2) for 48 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 95%, the yield was 81% and the cis:trans ratio was 0.3:1.
Reaction SMILES: [C:1]([N:18]=[C:19]=[S:20])(=[O:17])[O:2][CH2:3][CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[NH2:21][C@:22]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][O:24][CH2:23]1>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C@@:22]1([NH:21][C:19]([NH:18][C:1](=[O:17])[O:2][CH2:3][CH:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)=[S:20])[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9H-Fluoren-9-ylmethyl carbonisothiocyanatidate (Fmoc-isothiocyanate) (827 mg, 2.94 mmol) was added to a solution of [(3S,4R)-3-amino-3-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C11) (650 mg, 2.67 mmol) in dichloromethane (10 mL), and the reaction mixture was allowed to stir for 4 hours at room temperature. Removal of solvent in vacuo provided a paste, which was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to afford the product. Yield: 1.17 g, 2.23 mmol, 84%. LCMS m/z 525.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[O:32]=[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Yield: 84.3 %

Procedure:
To 1.44 g (3.17 mmol) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid ethyl ester in 100 ml of hot methanol was added 3.5 ml (3.5 mmol) of 1N NaOH. The mixture was heated on a steam bath for 5 minutes, water (20 ml) was added and the solvents were removed at reduced pressure. Water (100 ml) and 7.0 ml of 1.0N HCl were added to the residue and the product was extracted with methylene chloride-THF (4:1). The dried extract was concentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 1.14 g (84% yield, mp 98°-100°) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.CCN(S(F)(F)[F:26])CC.O>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][F:26])[CH2:13][CH2:12]1
Reactant: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The above 2-(4-(1,4-dioxaspiro[4.5]decyl)cyclohexyl)ethanol (20 g, 70.8 mmol) was dissolved in dichloromethane (70 ml), followed by dropwise adding to the solution, DAST (13 g, 80.7 mmol), stirring at 0° C. for one hour, adding water to the reaction solution, washing the resulting organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, purifying the residue according to column chromatography using heptane/ethyl acetate as a developing solvent, on silica gel, to obtain 1-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)-2-fluoroethane, adding thereto formic acid (80 ml), refluxing the mixture for 2 hours, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate, distilling off the solvent, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (8.0 g, 35.3 mmol). The yield of this product from 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol was 49.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sccc2c1
Product: BrCc1ccc2sccc2c1

Procedure:
5-Bromomethylbenzo[b]thiophene was prepared from 5-methylbenzo[b]thiophene and N-bromosuccinimide as in Example 1 except that the reaction was refluxed 15 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:19]([C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[Cl:9])[CH:16]=2)=[O:20])[CH:4]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCc1cccnc1
Agent: [Li+]
Product: O=C(NCc1cccnc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 3-aminomethylpyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:13]=[C:14]([CH2:18]O)[CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.O=S(Cl)[Cl:22]>C(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Cl:22])[CH:13]=3)[C:6]=2[S:10][CH:9]=1
Reactant: Nc1ncc(-c2cccc(CO)c2)c2scc(Br)c12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(-c2cccc(CCl)c2)c2scc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of example 673A (550 mg, 1.64 mmol) in CHCl3 (5 mL) was treated with SOCl2 (5 mL), stirred at room temperature for 3 hours then concentrated to give the title compound. MS (ESI (+)) m/e 352.7, 354.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39]C)=[O:37]>C1COCC1>[C:36](=[O:37])([O:38][CH3:39])[O:15][C:14](=[O:16])[CH2:13][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC(=O)C[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2 g (5.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl) amino]hexanoic acid and 0.56 g (5.73 mmol) of triethylamine are dissolved in 30 ml of THF under argon and cooled to 0° C. 0.59 g (5.73 mmol) of ethyl chloroformate are added, and the mixture is stirred at 0° C. for 3 hours. The reaction mixture is filtered through kieselguhr, and the filtrate is reacted directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:34][S:35]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOS(C)(=O)=O)C2
Reaction time: 0.25 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.95 g) and triethylamine (1.11 ml) in acetonitrile (20 ml) was dropwise added methanesufonyl chloride (0.494 ml) with cooling with ice. After the stirring was continued for 15 min, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (2.36 g) as an oil.