Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)=O.[OH-].[K+]>C(O)C.O>[CH3:3][NH:4][N:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1
Reactant: CCOC(=O)c1cn(NCC=O)c2cc3c(cc2c1=O)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(NC)c2cc3c(cc2c1=O)OCO3
Yield: 82.2 %

Procedure:
To a suspension of 4.1 g (0.013 mole) of ethyl 5,8-dihydro-5-[(formyl)methylamino]-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 6) in 40 ml of hot absolute ethanol was added a solution of 0.8 g (0.013 mole) of potassium hydroxide (85%) in 2.6 ml of water. The mixture was heated at near the boiling point of the ethanol for about 10 minutes and then chilled in an ice bath. The solid product was collected by filtration and washed with absolute ethanol and ether. After a further washing with water, tetrahydrofuran and ether and drying at 0.1 mm overnight there was obtained 3.1 g of ethyl 5,8-dihydro-5-(methylamino)-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate, colorless crystals, m.p. 211°-218° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[N-:11]=[C:12]=[O:13]>>[CH3:3][CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:13]
Reactant: O=c1[nH]sc2ccccc12
Reactant: [N-]=C=O
Product: CC(C)CCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6f was synthesized from benzo[d]isothiazol-3-one and isocyanate 4a′ as a white solid. mp 49-51° C.; IR(CHCl3) 3289, 1711, 1662, 1538 cm−1; 1H-NMR (DMSO-d6) δ0.84 (d, J=6.6 Hz, 6H), 1.13-1.20 (m, 2H), 1.26-1.32 (m, 2H), 1.47-1.55 (m, 3H), 3.28-3.34 (m, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 8.84 (br t, J=5.5 Hz, 1H); ESIMS m/e 293 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][C:28]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:32]
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314 (M+H).
Reaction SMILES: C[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.BrBr.[C:16]([NH:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])[CH3:17].[H-].[Na+].[CH3:33]N(C=O)C>CCOC(C)=O.C1C=CC=CC=1.O>[N:9]1[CH:10]=[C:11]([CH2:33][C:20]([NH:19][C:16](=[O:18])[CH3:17])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=[CH:13][C:8]=1[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Cc1cccnc1-c1ccccn1
Agent: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(-c2ccccn2)nc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Methyl-2,2′-bipyridine (1.7 g, 10 mmol) in a mixed solvent (100 mL) of water and benzene (1:1) was irradiated and refluxed using a halogen lamp (150 W). Bromine (1.6 g, 10 mmol) was added and the mixture was heated to reflux for 30 min. The solution was concentrated under reduced ressure and dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to afford the crude brominated product. A mixture of diethyl acetamidomalonate (2.6 g, 12 mmol) and sodium hydride (0.48 g, 12 mmol, 60% in mineral oil) in dry DMF (50 mL) was stirred for 30 min at 0° C. To the solution was added the crude product in dry DMF (20 mL) at 0° C. and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (200 mL) and washed with a 10% aqueous sodium thiosulfate solution (2×150 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0.5% MeOH in CH2Cl2) to give diethyl 2-(2,2′-bipyridine-5-ylmethyl)-2-acetamidomalonate (2.5 g, 65%) as a white solid. 1H-NMR (500 MHz, CDCl3): 1.38 (m, 6H), 2.15 (s, 3H), 3.81 (s, 2H), 4.35 (m, 4H), 6.68 (s, 1H), 7.36 (dd, 1H), 7.55 (dd, 1H), 7.87 (m, 1H), 8.36 (d, 1H), 8.41 (d, 1H), 8.42 (d, 1H), 8.74 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[Li+].[CH3:15][CH:16]([N-]C(C)C)C.ICC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(C(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)CCC(C(C)C)CC1
Yield: 78.5 %

Procedure:
4-Isopropyl-cyclohexanecarboxylic acid methyl ester (1.1 g, 6 mmol) was alkylated using a method analogous to General Procedure F using LDA (9 mmol) and iodoethane (1.4 g, 9 mmol) in THF (20 mL) at −78° C. to RT to produce 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid methyl ester (1.0 g, 78% yield) as a mixture of isomers. Hydrolysis of this ester using KOH (12.5 mmol) in aqueous EtOH (1:1; 5 mL) at 150° C. for 2 hr in a pressurized vessel following a microwave method analogous to General Procedure G2 gave 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid (800 mg, 86% yield) as a mixture of isomers after workup by evaporation of the solvent, treatment with aq 2 N HCl, extractive workup, and evaporation of the solvent.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: C=CCCCCCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCCCc2ccccc2)cc1
Yield: 53.9 %

Procedure:
General procedure M was used to convert 5.08 mmol of 15 and 5.59 mmol of 1-bromo-4-nitrobenzene to 2.74 mmol (54%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:10]([Cl:13])(Cl)=[O:11].C(Cl)Cl.[OH2:17]>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([Cl:13])(=[O:11])=[O:17])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O
Reactant: O=S(Cl)Cl
Reactant: c1ccc2c(c1)CCO2
Solvent: ClCCCl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Temperature: 85 °C
Yield: 100 %

Procedure:
3.56 g (29.6 mmol) 2,3-dihydrobenzofuran was added to a slurry of 5.44 g (35.5 mmol) sulfur trioxide-N,N-dimethylformamide complex in 12 mL 1,2-dichloroethane under argon. The reaction was heated to 85° C. for 1 hour and then cooled to room temperature. Thionyl chloride (2.6 mL, 35.5 mmol, 1.2 eq) was added dropwise and the reaction was slowly heated over the course of one hour, by which time it had reached 75° C. The mixture was allowed to cool to room temperature and 100 mL of methylene chloride and 100 mL water were added. The organic extract was separated, dried over magnesium sulfate, filtered and evaporated to afford 6.56 g (100%) of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rf chloroform/hexanes=1/1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: Fc1cc(Br)cc2c1NCC2
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCc2cc(Br)cc(F)c21
Yield: 60.2 %

Procedure:
This compound was prepared using the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 5-bromo-7-fluoroindoline (0.21 g, 0.97 mmol) and ethanesulfonyl chloride (0.18 mL, 1.9 mmol) to provide 5-bromo-1-(ethylsulfonyl)-7-fluoroindoline (0.18 g). MS (ES) m/z 307.6; HPLC purity 98.4% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: CO[CH:3]=[CH:4][C:5]1[CH:38]=[CH:37][C:8]([O:9][C@@H:10]2[CH2:14][N:13]([C:15]([N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH3:19])=[O:16])[C@H:12]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:11]2)=[CH:7][CH:6]=1.[NH2:39][C:40]1[CH:45]=[C:44]([Cl:46])[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:42][C:41]=1[S:51]([NH2:54])(=[O:53])=[O:52]>C(#N)C>[NH2:50][S:47]([C:43]1[C:44]([Cl:46])=[CH:45][C:40]2[NH:39][CH:3]([CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:9][C@@H:10]4[CH2:14][N:13]([C:15]([N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH3:19])=[O:16])[C@H:12]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:11]4)=[CH:37][CH:38]=3)[NH:54][S:51](=[O:52])(=[O:53])[C:41]=2[CH:42]=1)(=[O:48])=[O:49]
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(C=COC)cc2)C[C@H]1C(=O)OCc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Solvent: CC#N
Product: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(CC3Nc4cc(Cl)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)OCc1ccccc1

Procedure:
The diphenylmethyl ester product from part (c) in acetonitrile is reacted with a solution of 4-amino-6-chloro-1,3-benzenedisulfonamide in acetonitrile according to the procedure of 1(c) to give (cis)-4-[4-[[7-(aminosulfonyl)-6-chloro-3,4-dihydro-1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.[OH-].[NH4+]>C(O)C>[C:1]1([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc(-c3ccc(N4CCNCC4)nc3)[nH]2)cc1
Reactant: Clc1ncccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(-c2c[nH]c(-c3ccc(N4CCN(c5ncccn5)CC4)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.2 %

Procedure:
(Reference: J. Am. Chem. Soc. 1954, 1484) A solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (0.16 g, 0.52 mmol), triethylamine (0.22 ml, 0.16 g, 1.58 mmol, 3.0 equiv) and 2-chloro-pyrimidine (0.90 mg, 0.79 mmol, 1.5 equiv) in absolute ethanol (5 ml) under nitrogen atmosphere was heated at reflux for 1 hour, after which additional triethylamine (0.22 ml, 0.16 g, 1.58 mmol, 3.0 equiv) and 2-chloro-pyrimidine (0.90 mg, 0.79 mmol, 1.5 equiv) were added. The reaction was heated at reflux for an additional 1.5 hour, then stirred at room temperature for two days. The mixture was basified to pH 10 with concentrated ammonium hydroxide, and then concentrated in vacuo. The residue was partitioned between water (20 ml) and ethyl acetate (50 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a solid, which was triturated with ether to give the desired product (0.15 g, 74%). MS m/z 446 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[SH:11][CH2:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:14]1=[O:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([S:11][CH2:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:14]1=[O:15])=[O:6]
Reactant: O=C1OCC(c2ccccc2)C1CS
Reactant: O=C(O)c1ccccc1F
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(SCC1C(=O)OCC1c1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To a solution of 1.2 g of o-fluorobenzoic acid and 1.5 g of α-mercaptomethyl-β-phenyl-γ-butyrolactone in 20 ml of dimethylformamide were added 1.9 ml of diphenylphosphoryl azide (DPPA) and then 1.2 ml of triethylamine under ice-cooling. Then, the mixture was raised to a room temperature and stirred for 18 hours. After completion of the reaciton, the reaction mixture was diluted with 200 ml of ethyl ether, washed with 5% hydrochloric acid, saturated aqueous sodium hydrogencarbonate, and saturated saline, dried over magnesium sulfate and the solvent was then distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 1.6 g (yield 67%) of the title compound.
Reaction SMILES: [Na].C([O:5][C@@H:6]1[C@@H:10]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2Br)[CH2:9][C@@H:8]([CH2:23][O:24]C(=O)C)[C@@H:7]1[O:28]C(=O)C)(=O)C.[CH3:32][O-:33].[Na+].Cl>CO>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([C@@H:10]3[C@@H:6]([OH:5])[C@@H:7]([OH:28])[C@H:8]([CH2:23][OH:24])[CH2:9]3)[C:12]([O:33][CH3:32])=[N:13][C:14]=2[CH:19]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium (spheres, 0.10 g, 4.8 mequiv) were added to dry methanol (15 mL). (±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.560 g, 0.958 mmol) was added to the sodium methoxide in methanol and the solution stirred at ambient temperature under nitrogen for 5 hours. The solution was then neutralized with 1N hydrochloric acid and volatiles removed in vacuo. The residual solid was chromatographed on silica gel. (±)-(1R*,2S*,3S*,5S*)-5-(5,6-Dichloro-2-methoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 10% methanol-chloroform as a white powder, after trituration with diethyl ether (0.211 g, 64%), m.p. 204°-206° C. dec; 1H-NMR(DMSO-d6) δ: 7.82 and 7.67 (both s, 2, aromatic CH), 4.9 (m, 2,2 OH), 4.7-4.6 (m overlapping d at 4.61, J=4.1 Hz, 2 total, NCH and OH), 4.4-4.3 (m, 1, OCH), 4.11 (s, 3, OCH3), 3.8 (m, 1, OCH), 3.6-3.4 (m, 2, OCH2), 2.1-2.0 (m, 2, CH2), 1.9-1.8 (m, 1, CH); mass spectrum (CI): 347(M+1).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10](O)=[O:11])=[C:8](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(/C=C/c2ccccc2)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1noc(/C=C/c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 60 h
Yield: 103.9 %

Procedure:
To a solution of 3-butyl-5-([E]-styryl)-isoxazole-4-carboxylic acid (7.0 g, 25.8 mmol) and triethylamine (3.8 mL, 27.0 mmol) in THF (30 mL) was added at 0° C. ethyl chloroformate (2.6 mL, 27.0 mmol). After 1 h the triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The filtrate was concentrated, the residue taken up in ethanol (70 mL) and added to a solution of sodium borohydride (2.4 g, 63.4 mmol) in water (35 mL) at 0° C. After stirring at room temperature for 2.5 days, the reaction was quenched with aqueous sodium hydroxyde (1 M, 40 mL) and extracted twice with tert-butylmethylether. The combined phases were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated to a yellow oil and purified by flash chromatography (silica, dichloromethane:methanol 100:0 to 97:3) to afford the title compound (6.9 g, 98%) as an orange oil. MS: m/e=258.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1O>>[OH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCCCc1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCO)cc1

Procedure:
Analogously to Method F, 224 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 1.28 g of 2-(3-hydroxypropyl)phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.41 (2:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:15]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(I)c2c(c1)CNC1(CCCCC1)O2
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (1.5 g., 0.005 mole), cyclohexanone (0.5 g., 0.005 mole), and magnesium sulfate (0.5 g.) in tetrahydrofurane (50 ml.) is kept under nitrogen at 20°-25° C., for 16 hours. The magnesium sulfate is removed and the filtrate evaporated to dryness. The residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazine-2,1'-cyclohexane] (1.4 g.), m.p. 112°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16](C(O)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[O:29][CH3:30])[CH:3]=1.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[N:66]([CH:68]=[O:69])C>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:68]([NH2:66])=[O:69])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[O:29][CH3:30])[CH:3]=1
Reactant: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.21 g 4-[4-Fluoro-2-((1R,2R)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 5 ml ammonia 0.5 M in dioxane, 0.22 g HATU, 0.10 ml DIPEA and 2 ml DMF was stirred at rt overnight. The reaction mixture was diluted with water and filtered. The solid was dried in vacuo at 65° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][NH:46][CH2:47][C@@H:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)[CH2:44][CH2:43]1>CN(C=O)C.C(Cl)Cl>[CH:42]1([CH2:45][NH:46][CH2:47][C@@H:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:43][CH2:44]1
Reactant: C1CN[C@H](CNCC2CC2)C1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC[C@H]2CNCC2CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (80 mg, 0.22 mmol), EDC (80 mg), HOBt (30 mg) in DMF (4 mL) was added TEA (0.08 mL) and cyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL). The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].C(Cl)(=O)C(Cl)=O.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].C(N(C(C)C)C(C)C)C.CN(C1C=CC=CN=1)C>CN(C)C=O.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)NS(C)(=O)=O)c3c2)c1=O
Yield: 13.5 %

Procedure:
N,N-Dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (2.00 g, 0.00484 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 6.05 ml, 0.0121 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. Methylsulfonamide (0.690 g, 0.00726 mol) is added, followed by ethyldiisopropylamine (0.940 g, 0.00727 mol) and dimethylaminopyridine (0.100 g). The resultant mixture is stirred at room temperature and filtered. The filtrate is concentrated in vacuo and the residue is filtered through silica gel with hexanes:ethyl acetate. The filtrate is concentrated in vacuo to a tan solid. The solid is suspended in methylene chloride, stirred, and refiltered to give the title compound as a white solid (0.320 g, 13.5%, mp 264-265° C.).