Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C#Cc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cccc2ccccc12)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 37 %

Procedure:
The title compound was synthesized from naphthalene-1-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 37% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 8.32 (m, 1H), 7.85 (m, 2H), 7.47 (m, 3H), 7.27 (m, 2.5H), 6.95 (m, 3H), 6.72 (m, 1.5H), 6.58 (m, 0.5H), 6.35 (m, 1.5H), 4.27 (m, 2H), 4.03 (m, 2H), 3.69 (m, 2H), 3.14 (m, 2H), 2.67 (m, 2H), 1.86 (m, 2H), 1.45 (s, 9H), 1.18 (m, 3H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:19]1([C:25](=[O:29])[C:26](=[O:28])[CH3:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC>[OH:29][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:26](=[O:28])[CH3:27])[C:2]([CH3:3])([CH3:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: CCCCCCCCCCCCOC(=O)C(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCCOC(=O)C(C)(C)C(O)(C(C)=O)c1ccccc1
Yield: 31.6 %

Procedure:
The reaction of dodecyl isobutyrate (6.4 g, 0.025 mole) with 1-phenyl-1,2-propanedione (3.7 g, 0.025 mole) is conducted in the manner described in Example I. Thin layer chromatography of the crude reaction mixture indicated the presence of two main reaction products. High pressure liquid chromatography on silica gel using 2% ethyl acetate in hexane as the eluant yields pure dodecyl 3-hydroxy-2,2-dimethyl-4-oxo-3-phenylpentanoate (IVa) (3.2 g, 32%), b.p. 148° C. (Kugelrohr air bath temperature) at 0.005 mm Hg. Also recovered is pure dodecyl 3-hydroxy-2,2,3-trimethyl-4-oxo-4-phenylbutyrate (IVb) (3.5 g, 35%), b.p. 145° C. (Kugelrohr air bath temperature) at 0.005 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7](=[O:9])[CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCCCBr
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(C(C)=O)c1ccc(N)cc1
Reaction time: 0.12 h
Yield: 84 %

Procedure:
To a stirred solution of 4′-aminoacetanilide (1.00 g, 6.66 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in mineral oil; 0.28 g, 7.0 mmol). After 5-10 minutes, 1-bromohexane was added dropwise to the mixture. The reaction was stirred for one hour and then partitioned between ethyl acetate and water. The organic layer was washed with additional water, dried (sodium sulfate) and concentrated. The resulting brown oil was purified by flash chromatography over silica (methylene chloride/methanol) to afford 1.32 g (84%) of product as a viscous amber oil: 1H NMR (CDCl3) δ 6.91 (d, J=8.7 Hz, 1H), 6.68 (d, J=8.7Hz, 1H), 3.78 (br s, 2H), 3.61 (t, J=7.9Hz, 2H), 1.81 (s, 3H), 1.33-1.18 (m, 2H), 1.17-1.08 (m, 6H), 0.85 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.[O:26]1CCCC1.C(=O)(O)[O-].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH:2]([OH:26])[CH3:3])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCOC1
Reactant: C=CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: O=C([O-])O
Agent: OO
Solvent: CCO
Product: CC(O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 25.8 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 12B-e, 132 mg, 0.36 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a 1M solution of borane-tetrahydrofuran (0.7 mL, 0.72 mmol). The reaction mixture was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the solution was re-cooled to 0° C. and treated with ethanol (2 mL) followed by the slow addition of a mixture of a saturated aqueous sodium bicarbonate solution (6 mL) and 30% hydrogen peroxide (2 mL). The resulting mixture was allowed to slowly warm to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and was slowly quenched with a saturated aqueous sodium sulfite solution (20 mL). This mixture was extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×15 mL), dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexaneslethyl acetate) effected the separation of two spots, the first of the two product spots to elute off the column afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-(2-hydroxy-propyl)-urea (36 mg, 26%) as a white solid: mp 116.7-119.9° C.; EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1173.
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: BrCC1CC1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5

Procedure:
In an illustrative embodiment, a mixture of norbuprenorphine, a mild base, and cyclopropylmethyl bromide are heated in an oilbath at about 80-100° C. until the reaction is substantially complete. The reaction mixture is then added over 5 minutes to 160 ml of water, with mechanical stirring, yielding a gum. The mixture is stirred and filtered, and the filter cake is washed with water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, and then boiled in alcohol, cooled, and filtered to yield buprenorphine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(Cl)Cl.[CH3:66][S:67](Cl)(=[O:69])=[O:68]>>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was slowly added to a slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperidine-1-carboxylate (0.2611 g, 0.350 mmol) in DCM (5.00 mL, 78 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated (under vacuum to remove as much TFA as possible). The sticky residue was taken up in DCM (10.00 mL) and TEA (0.487 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.082 mL, 1.049 mmol) were slowly added at 0° C. The mixture was stirred for 1 h and then concentrated. The crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (ISCO Combiflash system, 10% to 50% ethyl acetate in hexanes) to give the desired product N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.1923 g, 0.265 mmol, 76% yield) as a yellow film. m/z (ESI, +ve ion) 725.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([CH:32]3[CH2:37][C:36]([CH3:39])([CH3:38])[O:35][C:34]([CH3:41])([CH3:40])[CH2:33]3)[N:9]=2)=[CH:4][CH2:3]1>CN(C=O)C>[CH3:1][C:2]1([CH3:42])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([CH:32]3[CH2:33][C:34]([CH3:41])([CH3:40])[O:35][C:36]([CH3:39])([CH3:38])[CH2:37]3)[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C3CC(C)(C)OC(C)(C)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CN(C)C=O
Product: CC1(C)CC=C(c2nc(C3CC(C)(C)OC(C)(C)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide (as prepared in the previous example, 17.6 g, 0.0290 mol) in DMF (30 mL) was added solid TBAF hydrate (16.6 g, 0.0630 mol ). The resulting mixture was heated at 70° C. overnight. The reaction mixture was allowed to cool to RT and partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, the aqueous layer was washed with EtOAc (3×100 mL) and the organic layers were combined, dried (Na2SO4) and concentrated. The resulting residue was dried under high vacuum to remove residual DMF. The residue was purified on silica gel (0-50% EtOAc/hexane). The resulting solid was then suspended in 25% ether/hexane and sonicated for 10 min. The product was collected by suction filtration and dried in a vacuum oven at 60° C. for 12 h to obtain the title compound as a white solid (10.2 g, 75%.) 1H-NMR (DMSO; 400 MHz): δ 14.26 (s, 1H), 10.02 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=8.3 Hz), 5.86 (br s, 1H), 3.23 (m, 1H), 2.40 (m, 2H), 1.91 (m, 2H), 1.74 (dd, 2H, J=12.9, 3.3 Hz), 1.48 (m, 4H), 1.30 (s, 6H), 1.15 (s, 6H), 0.96 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N5O2, 462.2 (M+H), found 462.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[NH3:23]>C(O)(C)C>[NH2:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1
Reactant: N
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Product: COc1ccc2c(N)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
A suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in 1.5 mL of 2M NH3 in isopropanol was heated in a sealed tube at 90 C overnight, then heated in a microwave reactor at 170 C for 24 h. The reaction was concentrated and purified by reverse-phase HPLC to give a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:14])=[CH2:13])[NH:6][C:5]2=[O:15].[Si]([CH:20]=[N+:21]=[N-:22])(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1([CH3:14])[CH2:13][CH:20]=[N:21][NH:22]1)[NH:6][C:5]2=[O:15]
Reactant: C=C(C)c1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: CC1(c2nc3ccc(Br)cc3c(=O)[nH]2)CC=NN1

Procedure:
Following the procedure described in the Example 7, using 6-bromo-2-isopropenyl-3H-quinazolin-4-one and TMSCHN2 as starting materials to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].Cl.OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[C:7]3[C:8]4[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:9]=4[S:10][C:6]=3[C:5]([C:19]#[N:20])=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnc(Cl)c2c1sc1cc(C(F)(F)F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(C(F)(F)F)ccc4c23)cc1
Reaction time: 0.17 h

Procedure:
A mixture containing 1-chloro-7-(trifluoromethyl) [1]benzothieno[3,2-c]pyridine-4-carbonitrile, 4-methoxybenzylamine (2.2 equiv), K2CO3 (2.5 equiv) in DMF (0.15 M) was placed in a microwave reactor at 120° C. for 10 min. The reaction was diluted with H2O, the pH adjusted to 4 with HCl and K2HPO4 solution, and the title product was isolated by filtration.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]4[NH:31][N:30]=[N:29][N:24]=4)=[CH:25][CH:26]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.144 g, 0.393 mmol) was reacted with NaN3 (0.128 g, 1.965 mmol) and NH4Cl (0.105 g, 1.965 mmol) in DMF (5 ml) to give the product (0.133 g, 0.325 mmol, 83%) as a white solid, dec. 214-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>ClCCl>[OH:20][CH:18]([CH2:16][Cl:17])[CH2:19][S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: ClCC1CO1
Reactant: S=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC(CCl)CSc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (14 mmol) and triethylamine (14 mmol) was stirred together in dichloromethane (30 ml) for 5 min before epichlorohydrin (15 mmol) was added. The mixture was stirred at room temperature for 3 h, the solvent evaporated, the residue triturated with water, the insoluble material extracted with chloroform, the dried (MgSO4) chloroform solution evaporated and the residue crystallized from chloroform:pet. ether; yield 30%, m.p. 99° C. 1H NMR (acetone-d6): δ3.3-3.8 (2CH2, m) 3.9-4.4 (CH, m), 4.6-4.7 (OH), 8.59 (H-4, H-6).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[C:26](=[O:28])=[O:27].Cl>>[CH:20]1([C:3]2[CH:4]=[C:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:6]=[C:7]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[C:2]=2[C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=O
Reactant: Brc1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Agent: Cl
Product: O=C(O)c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Yield: 80 %

Procedure:
A Grignard reagent was prepared from 28.4 g of 2-bromo-1,3,5-tricyclohexylbenzene (prepared in Synthesis Example 1-4) and poured to 300 g of dry ice, whereupon dry ice sublimated. Hydrochloric acid was added to the reaction mixture for quenching, followed by extraction with 200 g of isopropyl ether. The organic layer was taken out, washed with water, and combined with 150 g of 10 wt % sodium hydroxide aqueous solution. The aqueous layer was taken out, combined with 100 g of 35 wt % hydrochloric acid, and extracted with 200 g of diisopropyl ether. The organic layer was washed with water again, and concentrated under reduced pressure. The concentrate was crystallized from 150 g of hexane. The crystal precipitate was filtered and dried, obtaining the target compound, 2,4,6-tricyclohexylbenzoic acid. Amount 39.7 g, yield 80%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][CH3:2])=[CH:5][C:6]=2[CH2:12][CH2:11]1)(=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)CCNCC2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CCN(C(C)=O)CC2
Reaction time: 16 h

Procedure:
A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (4.3 g, 0.02 m) and sodium acetate (3.3 g, 0.04 m) in acetic anhydride (13 ml) was refluxed and stirred for 16 hours, concentrated in vacuo and partitioned between methylene chloride and water. The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 89°-90°.
Reaction SMILES: [CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:19]([O:22][C:23](=O)C)(=O)[CH3:20].C(OC(OCC)OCC)C>>[CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([C:6](=[CH:23][O:22][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1c(F)cc(F)c(F)c1C
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Yield: 90 %

Procedure:
To ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (3.2 g) are added acetic anhydride (3.0 g) and triethoxymethane (2.7 g) and the mixture is refluxed for 1 hour. After concentrating, ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) is obtained.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[O:8]1[CH2:9][CH2:10][CH:6]([C:4](=[O:5])[CH2:12][CH3:13])[CH2:7]1
Reactant: CON(C)C(=O)C1CCOC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (4.1 g) in THF (40 ml) was added ethylmagnesium bromide (3 M in ether, 13.0 ml) at 0° C. The reaction mixture was then slowly warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated 1 M HCl (10 ml), and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.0 g) as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]([O-])=[O:13].[Na+]>O.Cl>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: O=N[O-]
Reactant: Oc1cccc2cccnc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(O)c2ncccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of 8-hydroxyquinoline (58 g, 0.4 mol) in distilled water, concentrated hydrochloric acid (75 ml) and ice (200 g) was added NaNO2 (30 g) in water (100 ml) at 0-4° C. during 1 hr. The reaction mixture was kept at 0° C. overnight and then filtered by washing with cold water to give 5-nitroso-8-hydroxyquinoline hydrochloide (95%).
Reaction SMILES: [F:1][CH:2]([F:16])[C@H:3]1[CH2:8][C@H:7]([OH:9])[C@H:6]([NH:10]C(=O)C)[C@@H:5]([OH:14])[C@@H:4]1[OH:15].[OH-].[Na+]>CCO.O>[NH2:10][C@H:6]1[C@@H:7]([OH:9])[CH2:8][C@H:3]([CH:2]([F:1])[F:16])[C@@H:4]([OH:15])[C@@H:5]1[OH:14]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Yield: 30.8 %

Procedure:
To a solution of N-((1S,2R,3R,4S,6S)-4-(difluoromethyl)-2,3,6-trihydroxycyclohexyl)acetamide (176 mg, 1.48 mmol) in EtOH (2 mL) and water (3 mL) was added NaOH (736 mg, 18.4 mmol). The mixture was heated at reflux for 2 h. Solvents were evaporated and the residue was purified by silica gel column chromatography, eluted with 20% 2 M NH3 MeOH solution in DCM to give the product (1R,2R,3S,4S,6S)-3-amino-6-(difluoromethyl)cyclohexane-1,2,4-triol (90.0 mg, 62%) as a white solid.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C[O:9][C:10](=O)[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>ClCCl.CO.CCN(CC)CC>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10](=[O:9])[CH2:11][S:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCCCN
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 56 %

Procedure:
1,5-Diaminopentane (0.75 g, 7.21 mmol) was stirred while tritylsulfanyl-acetic acid methyl ester (2.53 g, 7.27 mmol) was added slowly. The mixture was heated at 100° C. for 2 h while methyl alcohol escaped. The product was isolated by column chromatography (dichloromethane/MeOH/Et3N=10/1/0.1) to provide 7-Amino-1-tritylsulfanyl-heptan-2-one (1.63 g, 54%). 1H NMR (300 MHz, CD3OD) δ 7.42-7.36 (m, 6H), 7.31-7.18 (m, 9H), 3.00 (t, J=6.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.42 (m, 4H), 1.27 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 171.1, 145.8, 130.9, 129.2, 128.2, 68.4, 42.5, 40.8, 37.4, 33.4, 30.1, 25.3.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1>>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[N:3]2
Reactant: Clc1ccc2c(Cl)cccc2n1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(c2ccc3c(Cl)cccc3n2)CC1

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 4.78 g (24.14 mmol) of 2-chloro-5-chloroquinoline (J. Med. Chem., 2002, 45, 3130-3137) and 3.43 g (26.55 mmol) of 2-(4-piperidyl)ethanol, 7 g of product are obtained in the form of an oil, which is used without further purification in the following step.