Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[CH3:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1ccc(O)c(C)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)cc2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,4-dimethylphenol: 1H-NMR (CDCl3) δ 8.56 (1H, d, J=2.8 Hz), 8.32 (1H, d, J=7.5 Hz), 8.11 (1H, d, J=2.6 Hz), 8.02–7.98 (2H, m), 7.43 (2H, d, J=8.3 Hz), 7.26–7.09 (2H, m), 6.99 (1H, d, J=8.1 Hz), 5.45–5.36 (1H, m), 3.90 (3H, s), 2.36 (3H, s), 2.10 (3H, s), 1.59 (3H, d, J=7.0 Hz); MS (ESI) m/z 439 (M+H)+, 437 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:15]([O:13][CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:16])[CH3:14]
Reactant: OC1CCC(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a mixture of 20.3 g (0.115 mol) of 4-phenylcyclohexanol, 14.2 ml (0.15 mol) of acetanhydride and 29 ml of triethylamine are added, with stirring and at ambient temperature, 2.3 g (0.02 mol) of 4-dimethylaminopyridine, a clear solution being produced in an exothermic reaction. This is heated to 80° C. for 3 hours and the reaction mixture is then poured into ice water. The crystalline product precipitated is suction filtered, dissolved in ether, washed with sodium bicarbonate solution, dried and evaporated down in vacuo. 23 g (92% of theory) of O-acetyl-4-phenylcyclohexanol are obtained. The product is obtained initially as an oil but crystallises when left to stand.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C@@:25]12[CH2:50][CH2:49][C@@:48]([C:52]([F:55])([F:54])[F:53])([OH:51])[CH2:47][C@H:26]1[CH2:27][CH2:28][C@H:29]([OH:46])[C:30]1[C:31]2=[CH:32][C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH:38]=1)[CH3:24].C([C@@]12CC[C@@](C(F)(F)F)(O)C[C@H]1CC[C@@H](O)C1C2=CC2C=NN(C3C=CC(F)=CC=3)C=2C=1)C.C([O-])(O)=O.[Na+]>CC#N.O.C(Cl)Cl>[CH2:23]([C@@:25]12[CH2:50][CH2:49][C@:48]([OH:51])([C:52]([F:55])([F:53])[F:54])[CH2:47][C@H:26]1[CH2:27][CH2:28][C:29](=[O:46])[C:30]1[C:31]2=[CH:32][C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37]=2[CH:38]=1)[CH3:24]
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CC[C@H](O)c1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CC[C@@H](O)c1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCC(=O)c1cc3c(cnn3-c3ccc(F)cc3)cc12
Reaction time: 1.5 h

Procedure:
Dess-Martin periodinane (0.017 g, 0.039 mmol) was added to a solution of (3R,4aR,7 S,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3,7-diol (61, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0079 g, 0.017 mmol), (3R,4aR,7R,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3,7-diol (62, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0061 g, 0.013 mmol), and DCM (0.300 mL) under a nitrogen atmosphere. After about 90 min, sat. aq. NaHCO3 (2 mL) and water (1 mL) were added. The mixture was extracted with EtOAc (2×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (4 g) using a gradient of 0-25% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford an ivory foam. The residue was dissolved in MeCN, treated with water, and concentrated under reduced pressure to remove MeCN. The mixture was frozen then lyophilized to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-7(9H)-one (63, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0124 g, 89% yield) of an ivory solid. LC/MS, method 2, Rt=2.54 min, MS m/z 461 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.41-8.38 (m, 1H), 7.93 (s, 1H), 7.84-7.75 (m, 2H), 7.54 (s, 1H), 7.48-7.39 (m, 2H), 5.94 (s, 1H), 2.86-2.74 (m, 1H), 2.70-2.59 (m, 1H), 2.26-2.14 (m, 1H), 2.09-1.84 (m, 5H), 1.81-1.59 (m, 4H), 1.54-1.40 (m, 1H), 0.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[Ni].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Cl
Agent: [Ni]
Solvent: CCO
Solvent: NCCN
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 2-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 0.54 g of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (50 kgf/cm2) for 24 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 100%, the yield was 88.9% and the cis:trans ratio was 1.4:1. The analytical data of the title compound are as follows.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH3:31])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH3:23])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH3:31])=[CH:14][O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)[CH3:23]
Reactant: CCc1ccccc1C(=COCCN1CCC=C(C(=O)OC)C1)c1ccccc1CC
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccccc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
1-(2-((2,2-bis(2-Ethylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.40 g, 0.00323 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (10 ml) and 12 N sodium hydroxide solution (0.8 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.80 g, 57%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[CH:22][CH:21]=1.C[Si]([N:34]=[C:35]=[S:36])(C)C.Cl>C1C=CC=CC=1.O>[CH3:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([C:35](=[S:36])[NH2:34])[C:24]=2[N:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1ccnc2c1CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: Cc1ccnc2c1CCCC2C(N)=S
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A stirred solution of di-isopropylamine (12.2 ml, 0.085 mol) in benzene (100 ml) at 0° C was treated dropwise with a 9% w/v solution of butyl lithium in hexane (62 ml, 0.085 mol). After 1 hour at 0° C, 4-methyl-5,6,7,8-tetrahydroquinoline (12.8 g, 0.085 mol) was added dropwise and then after a further hour the anion was treated dropwise with trimethylsilyl isothiocyanate (12.2 ml, 0.095 mol). After 0.5 hours at 0° C and 0.5 hours at room temperature the reaction mixture was diluted with water (50 ml) and the pH adjusted to 2.0 with conc. HCl. The aqueous layer was separated and adjusted to pH 10.0 with solid sodium carbonate and extracted with chloroform (3 × 50 ml) and the combined extracts were dried over MgSO4, filtered and the solvent was removed in vacuo. The residual oil was triturated with n-hexane to give 4-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (3.4g, 19%). The hydrochloride was prepared by dissolving in hot iso-propyl alcohol adding excess ethereal HCl solution and allowing to crystallise to give 4-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide, hydrochloride m.p. 212-3° C. (Found: C, 54.9; H, 6.4; N, 11.5. C11H14N2S. HCl requires C, 54.4; H, 6.2; N, 11.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[F:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>C(OCC)C>[F:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Cc1ccc(C=O)c(F)c1
Reactant: Cc1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccnc(C(O)c2ccc(C)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-methylpyridine (600 mg) in diethyl ether (20 mL) at −78° C. is added a 2.3M solution of butyllithium in hexanes (1.52 mL). After stirring at this temperature for 1 hour 2-fluoro-4-methylbenzaldehyde is added and the mixture allowed to warm at room temperature. The reaction mixture is then hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-4-methylphenyl)(4-methyl-pyridin-2-yl)methanol as a pale yellow oil which solidifies on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=1[NH:10]C(=O)C)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2]
Reactant: COc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(N)c([N+](=O)[O-])c1
Yield: 90.8 %

Procedure:
To a 200 mL flask equipped with reflux condenser, thermometer, and stirring bar was added 3-nitro-4-acetylamino-1-methoxybenzene (22 g., 0.11 mole), 34.4 mL of 10% aqueous alcoholic sodium hydroxide. The stirring mixture produced the precipitation of red solid over 3 hours. The precipitate was filtered and washed with ice water and recrystallized from MeOH to give 3-nitro-4-amino-anisole (16.8 g., 95% yield, m.p. 123°-124° C.). Spectral characterizations of these materials were identical with literature information. Kim, et al., J. Korean Chem. Soc., 1987, 31: 464-470.
Reaction SMILES: [C:1]([NH:10][OH:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O[CH:15](OCC)[CH2:16][CH2:17][CH2:18]Cl)C>C(O)(=O)C>[O:11]1[N:10]2[CH:18]([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]2=[O:9])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(NO)c1ccccc1O
Reactant: CCOC(CCCCl)OCC
Solvent: CC(=O)O
Product: O=C1c2ccccc2OC2CCCON12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Salicylhydroxamic acid (30 g.) and 36 g. of 4-chlorobutyraldehyde diethyl acetal were allowed to react in acetic acid as described in Example 1. The reaction mixture was transferred to an ice-water mixture, stirred well, and decanted to remove the aqueous layer. The oil was washed again with water and allowed to stand at room temperature whereupon crystallization occurred. Aqueous solution of ammonium hydroxide was added, mixture was warmed and stirred and then allowed to stand overnight at room temperature. The aqueous solution was decanted from the partially crystallized oil and the latter was triturated with ethanol yielding 9.5 g. of solid melting at 137.5°-139.5° C. After recrystallization from methanol, the product (7 g.) melted at 139°-141° C.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:19][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC1(N)CCCC1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCCC1
Yield: 62.1 %

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (375 mg, 2.31 mmol) and (1-methylcyclopentyl)amine (229 mg, 2.31 mmol) in 10 ml of absolute ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to dryness and the residue (532 mg) purified by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol: NH4OH) to afford 375 mg of product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]=1[CH3:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)(=[O:19])=[O:20])=[CH:16][CH:17]=3)[C:3]=2[CH3:27])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1sc(Br)c(C)c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared by following process provided in example 3 step 4, using 48b and (4-chlorophenyl)boronic acid as reactants.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[C:8]1([C:4]2[N:3]=[C:2]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]4=[N:21][CH:20]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccc4)n3)cnc2n1
Yield: 34.4 %

Procedure:
2-Bromo-6-phenylpyridine (0.17 g, 0.7 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.9 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-10%) and trituration with ethyl acetate gave 3-(6-phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (82 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.39 (1H, d, J 7), 7.53 (3H, m), 7.70 (1H, d, J 8), 7.78 (1H, d, J 8), 7.91 (1H, dd, J 8 and 8), 8.01 (2H, d, J 8), 8.53 (1H, s), 10.62 (1H, d, J 7); m/z (ES+) 341 (M++H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:25]([CH:24]2[CH2:23][CH2:27]2)[OH:26])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: O=C1COCCN1Cc1ccccc1
Agent: [Li+]
Product: O=C1C(C(O)C2CC2)OCCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-morpholin-3-one (9.5 g, 50 mmol) in THF (200 mL) is added lithium diisopropylamide (2M solution in THE, 27 mL, 54 mmol, 1.1 eq) dropwise over 20 minutes at −78° C. followed by slow addition of cyclopropyl methylaldehyde (3.85 mL, 55 mmol, 1.1 eq). After stirring at −78° C. for one hour the reaction mixture is allowed to warm to room temperature and stirred for another 6 hours. The reaction is quenched by addition of EtOAc and brine. The aqueous layer is extracted with EtOAc, the combined organic layers are dried over magnesium sulphate and reduced in vacuo. Purification using automated column chromatography (DCM/MeOH, 100/0 to 85/15 [v/v]) gives 75 in 70% purity with 4-benzyl-morpholin-3-one as the major impurity. This product is directly used in the next step. MW 261.32; C15H19NO3; LCMS (6 min method) m/z 261.32 [M+H]+, RT 2.23
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].C1(NN)C=CC=CC=1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:36]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: NNc1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (500 mg, 1.7 mmol), and copper (II) trifluoromethanesulfonate (360 mg, 1.0 mmol) were added in an autoclave, and the mixture was cooled to a temperature below −30° C., and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) was charged under elevated pressure. Phenylhydrazine (0.11 g, 1.0 mmol) was added to this mixture under elevated pressure, and then temperature was raised to 30° C. Then, a mixed solution containing 97.6% of ethyl diazoacetate (11.69 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (166.7 g). The content of was 3.95% (yield based on ethyl diazoacetate: 39.5%), and the ratio of cis-isomer/trans-isomer was 65.0/35.0. The optical purity of the cis-isomer was 98% e.e. (1S,2R) or more, and the optical purity of the trans-isomer was 94% e.e. (1S,2S).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:6]([CH:32]=1)[CH2:7][N:8]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[C:6]([CH:32]=1)[CH2:7][N:8]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(C(=O)O)cc2)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Solvent: O=CO
Product: O=C(O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)O)cc2)cc1
Reaction time: 18 h
Yield: 75 %

Procedure:
tert-Butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-carboxybenzyl)-amino]benzoate (example 3) (500 mg) was suspended in formic acid (2 ml) and heated on a steam bath until a clear solution was obtained. This solution was left at ambient temperature for 18 hours and the resulting solid filtered, washed with formic acid (2×1 ml) and dried under vacuum at 60° C. to give the title product (340 mg) m.p. 271° C.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[N:9][C:10]2[N:15]=[N:14][C:13]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O1CCCC1.[Pd]>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][O:16][C:13]1[N:14]=[N:15][C:10]([NH:9][NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:12]=1
Reactant: OCC(O)COc1ccc(N=NC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC(O)COc1ccc(NNC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 58.4 %

Procedure:
Into a solution of (RS)-3-[(6-triphenylmethylazo-3-pyridazinyl)oxy]-1.2-propanediol (5.45 g) in 95% ethanol (100 ml) and tetrahydrofuran (50 ml) containing 5% palladium on charcoal (1.1 g) hydrogen was bubbled, at room temperature, for 16 hours. Removal of the catalyst and evaporation of the solvent gave a residue which was crystallized from 2-propanol to yield 3.2 g of the title compound. m.p. 174°-176° C. Mass spectrum (E.I. 70 eV, 1.5 mA), m/z=412 (M-N2H2)+, 338 (M-C3H8N2O2)+, 243 (Ph3C)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C=NCCCl
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
2-Chloroethylisocyanate (10.0 g, 94 mmol) was added dropwise to a mixture of 4-aminopyridine (6.0 g, 63 mmol) and toluene (40 mL) at 0° C., and the mixture was stirred at room temperature for 6 hrs. The precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (11.1 g, 87%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:35])([CH3:34])[C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C(OC(C)(C)C)=O)=[N:6]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:58][Si](C)(C)C)(C)C.[Li+].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.[Pd].CO>[NH2:58][C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:34])([CH3:35])[C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([NH:10][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:6]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC(C)(C)C21COC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Under argon atmosphere, to a mixture of di-tert-butyl (6′-bromo-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (1.00 g, 1.81 mmol), bis(dibenzylideneacetone)palladium (0) (104 mg, 0.181 mmol) and tri-tert-butylphosphonium tetrafluoroborate (53.5 mg, 0.181 mmol) was added lithium bis(trimethylsilyl)amide (1.0 M in toluene, 9.03 mL, 9.03 mmol) at ambient temperature. After stirring for 1 hour at 100° C., the reaction mixture was cooled down to ambient temperature. To the mixture were added 1.0 M hydrochloric acid (9.0 mL) and MeOH (9.0 mL) and the mixture was stirred for 30 minutes at ambient temperature. After extraction of the mixture with CHCl3, the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated at reduced pressure and the residue was purified by column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl (6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (616 mg).