Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol (2.65 g, 7.0 mmol), methyl 3-bromobenzoate (3.01 g, 14.0 mmol), CuO (1.01 g, 12.6 mol), and K2CO3 (1.93 g, 14.0 mmol) in dry pyridine (17.5 mL) are heated under nitrogen at 120° C. for 48 h. The cooled reaction is diluted with water (100 mL) and extracted with ether (2×100 mL). The dried (MgSO4) extracts are concentrated to a dark oil which is chromatographed on silica gel using 20:80 ethyl acetate:hexane as eluent isolating the title compound as a colorless tacky solid (Rf˜0.3, 1.53 g). MS (ESI) m/z 514; HRMS: calcd for C31H22F3NO3+H+, 514.16245; found (ESI, [M+H]+), 514.1638.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]#[N:5].[NH2:17][S:18](N)(=[O:20])=[O:19]>O1CCOCC1>[S:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:17]
Reactant: C[Si](C)(C)CC#Cc1cccc(N)c1C#N
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CC#Cc1cccc(NS(N)(=O)=O)c1C#N
Yield: 5 %

Procedure:
A solution of 2-amino-6-(3-(trimethylsilyl)prop-1-ynyl)benzonitrile (Example 253b) (557 mg, 2.0 mmol) and NH2SO2NH2 (0.96 g, 10 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 70% EtOAc in hexanes to give the title compound (31 mg, 5%) as a white solid. MS 308 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>CCCCCC.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:27]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@H:19]([OH:22])[CH2:20][OH:21])[CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Solvent: CCO
Solvent: CCCCCC
Product: O=C(C(C(=O)c1cccc([C@H](O)CO)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1

Procedure:
Resolution of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-(1,2-dihydroxyethyl)phenyl]propane-1,3-dione was carried out in the usual way using a chiral column: CHIRALCEL OD-H (trade name, Daicel Chemical Industries) and an eluent: hexane/ethanol 3:1. 1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1S)-1,2-dihydroxyethyl]phenyl}propane-1,3-dione (Example 13-1) was obtained as the isomer having shorter retention time.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([C:25](=[O:27])[CH3:26])[CH:17]=[CH:18][C:19]=1[C:20]1[N:21]=[CH:22][S:23][CH:24]=1.Cl>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:26][C:25]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[C:14]([CH3:13])[CH:15]=1)=[O:27]
Reactant: CC(=O)c1ccc(-c2cscn2)c(C)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl trifluoroacetate (500 mg, 3.52 mmol) in tert-butyl methyl ether (4 ml) was added sodium methoxide (28 wt. % solution in methanol; 0.9 ml, 4.0 mmol) over 2 min. A solution of 1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone from step 4 (714 mg, 3.33 mmol) in t-butylmethylether (6 ml) was added dropwise over 5 minutes, and the mixture was stirred for 20 hours. 2N HCl (10 ml) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried_over MgSO4, and concentrated in vacuo, and the residue was used for next reaction without further purification. (1.05 g, 99% yield).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:35])[C:13]([NH:23][C:24](=[O:34])[CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:43]>O1CCOCC1>[ClH:43].[NH2:26][CH2:25][C:24]([NH:23][C:13]1[C:12](=[O:35])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:36])[CH:10]=2)[N:15]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=1)=[O:34]
Reactant: CCC(CC)n1cc(NC(=O)CNC(=O)OC(C)(C)C)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1cc(NC(=O)CN)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 2.9 ml dioxane solution of tert-butyl (2-{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-2-oxoethyl)carbamate was added 3.0 ml of a 4M hydrogen chloride dioxane solution, followed by overnight stirring at room temperature. The insoluble materials were collected by filtration to obtain 550 mg of 2-amino-N-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acetamide hydrochloride.
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=1[OH:28])(=[O:19])=[O:18])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]=[C:38]=[O:39]>>[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]([OH:28])=[C:22]([NH:27][C:38]([NH:37][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([Cl:36])[C:30]=2[Cl:29])=[O:39])[CH:23]=[CH:24][C:25]=1[Cl:26])(=[O:19])=[O:18])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 54.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[3-(tert-butoxycarbonylamino)propyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (110 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (65 mg, 0.35 mmol) were coupled to form the desired urea (90 mg, 55%). EI-MS (m/z) 565.64, 567.74, 569.60 (M−).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)c1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)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 A11 using 5-methyl-2-(1H-pyrazol-1-yl)benzoic acid. MS (ESI) 313 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2([O:13]C3CCCCO3)[CH2:12][CH2:11]2)[N:5]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2([OH:13])[CH2:12][CH2:11]2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccn(CC2(OC3CCCCO3)CC2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccn(CC2(O)CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
The 3-nitro-1-[1-(tetrahydro-pyran-2-yloxy)-cyclopropylmethyl]-1H-pyrazole (326 mg, 1.22 mmol) was dissolved in ethanol (7 mL) and p-toluene sulfonic acid (50 mg, 0.29 mmol) was added. After stirring at 25° C. for 1.5 h, the solution was concentrated in vacuo to give an oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) afforded 1-(3-nitro-pyrazol-1-ylmethyl)-cyclopropanol (158 mg, 71%) as an oil: H1-NMR (400 MHz, CDCl3) δ 0.81-0.86 (2H, m), 0.97-1.02 (2H, m), 2.78 (1H, bs), 4.31 (2H, s), 6.92 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz).
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Reactant: CCN1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 90.6 %

Procedure:
To a mixture of 1.1371 g (4.0 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.5129 g (4.0 mmole) of 4-amino-1-ethylpiperidine followed by 1.0119 g (10 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.0056 g 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide, which was used without further purification.
Reaction SMILES: S(O)(=O)(=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14]O)[CH2:12][C:11]2=[CH:16][CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][C:11]2=[CH:16][CH:17]=1
Reactant: COc1ccc2c(c1)C(CO)C2
Reactant: C1CCNCC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(CN1CCCCC1)C2

Procedure:
A solution of 5-methoxy-1-hydroxymethylbenzocyclobutene mesylate (38 g) and piperidine (45 ml) in toluene (180 ml) is refluxed under nitrogen for about 12 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo leaving a liquid residue which is used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:14]1.Cl.Cl.NC1C=CC(N2CCC[C@@H](C(N3CCCC3)=O)C2)=NC=1N.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:20])[CH2:14]2)[N:7]=1
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-nitropyrimidin-4-amine (670 mg, 3.84 mmol, 80% pure), (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (prepared by the method described in Steps 1 and 2 of Intermediate 1, 560 mg, 2.56 mmol) and triethylamine (0.761 mL, 5.46 mmol) in dimethylsulfoxide (5 mL) was heated to 100° C. for 5 h. The mixture was diluted with ethyl acetate (80 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude material was purified via flash chromatography (ethyl acetate/heptane: 40-70-100%) to afford (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow solid (420 mg). 1H NMR (500 MHz, DMSO-d6) δ 1.45 (t, 1H), 1.62 (d, 1H), 1.72-1.82 (m, 4H), 1.88 (d, 4H), 2.56 (br s, 1H), 2.90-3.04 (m, 2H), 3.28 (t, 2H), 3.37-3.62 (m, 2H), 4.59-4.87 (m, 2H), 8.00 (br s, 1H), 8.16 (br s, 1H), 8.90 (s, 1H); MS (ES+) (M+H) 321.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C@H:11]([CH2:24][CH3:25])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C@H:11]([CH2:24][CH3:25])[C@:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)([CH3:23])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc(N)c1
Reaction time: 2 h
Yield: 107.1 %

Procedure:
A suspension of [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (90 mg) in ethyl alcohol (2 ml), NEt3 (10 mg) and Pd/C (10%, 10 mg) was hydrogenated at normal pressure and 22° C. for 2 h. The mixture was filtered and the filtrate evaporated to give [(4S,5R)-4-(3-amino-phenyl)-5-ethyl-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (89 mg) as a colorless foam. MS (ESI): m/z=361.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].O>CC(N(C)C)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N:26]=[N+:27]=[N-:28])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(N=[N+]=[N-])cc2C(F)(F)F)C[C@@H]1OC
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid methyl ester (500 mg, 1.123 mmol, intermediate in the synthesis of example 58) in DMA (5 ml) was added sodium azide (146 mg, 2.246 mmol) and the reaction mixture was heated to 50° C. for 26 h. Then water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were dried (Na2SO4) and evaporated. The remaining brown oil was purified by silica gel chromatography (DCM/EtOAc 95:5) to obtain the title compound (351 mg, 77%) as light brown oil. MS (EI): 466.2 (M+OAc)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-acetate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoacetate according to general procedure D.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: C/C=C/C(=O)Cl
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC=CC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 6,7-dichloro-2,3-dihydro-2-benzofurancarboxylate (13.4 g, 0.05 mole) and crotonyl chloride (8.15 g, 0.09 mole) in CH2Cl2 (30 ml) cooled to 5° C. in an ice bath is added aluminum chloride (22.5 g, 0.17 mole) over a 10 minute period. The reaction mixture is stirred for 1 hour at 25° C. then for 20 minutes at reflux. The reaction mixture is poured into ice water, extracted into ether, washed with water and the ether evaporated in vacuo. The residue is treated with 10 N sodium hydroxide (100 ml) and the resultant sodium salt filtered and suspended in dilute hydrochloric acid which is extracted with ether (206 ml), washed with water, dried over magnesium sulfate, evaporated to 50 ml and treated with hexane to give 6,7-dichloro-2,3-dihydro-5-(1-oxo-2-butenyl)-2-benzofurancarboxylic acid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7]>>[C:6]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 70 °C

Procedure:
Chlorosulfonic acid (3 mL, 45 mmol) was added slowly to N-acetylindoline (1.0 g, 6.2 mmol), resulting in a strongly exothermic reaction. The mixture was then heated to 70° C. for 2 h. The mixture was allowed to cool to rt and was then poured onto crushed ice resulting in the formation of a cream precipitate that was isolated by filtration to give the title compound as a cream solid: yield; 1.34 g (52%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.93-7.91 (m, 1H), 7.41-7.40 (m, 1H), 7.40-7.38 (m, 1H), 4.06 (t, J=7.8 Hz, 2H), 3.09 (t, J=7.8 Hz, 2H), 2.13 (s, 3H).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([C:53](O)=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][N:29]([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:53]([CH:50]3[CH2:51][CH2:52][N:47]([C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[CH2:48][CH2:49]3)=[O:54])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCNCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCCCC2)CC1
Yield: 45.7 %

Procedure:
The compound 29 (89 mg), dimethylformamide (1 mL), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (44 mg), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (94 mg) and diisopropylethylamine (42 μL) were stirred at room temperature for overnight. The reaction solution was added aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol:aqueous ammonia=80:20:1) to obtain the title compound (56 mg) having the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:3][CH:2]=1.Cl.[NH2:22][C:23]1[C:24]2[C:34]([O:35][CH2:36][C@H:37]3[CH2:42][CH2:41][CH2:40][NH2+:39][CH2:38]3)=[CH:33][CH:32]=[CH:31][C:25]=2[NH:26][S:27](=[O:30])(=[O:29])[N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:22][C:23]1[C:24]2[C:34]([O:35][CH2:36][C@H:37]3[CH2:42][CH2:41][CH2:40][N:39]([C:9]([NH:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:20])[CH2:38]3)=[CH:33][CH:32]=[CH:31][C:25]=2[NH:26][S:27](=[O:29])(=[O:30])[N:28]=1
Reactant: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)NCc4ccncc4)C3)c21

Procedure:
A solution of 4-nitrophenyl (pyridin-4-ylmethyl)carbamate (Example 27d, 27.3 mg, 100 umol), (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 34.6 mg, 0.10 mmol) and K2CO3 in DMF (1 mL) was stirred at room temperature overnight. The resulting mixture was filtered and purified by preparative HPLC (10-90% acetonitrile in water) to provide the title product as a white solid. MS=445 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>C(OCC)C>[CH2:1]([O:8][C:9]1[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of 2-benzyloxy-thiophene (184 mg, 0.967 mmol) in diethyl ether (4 mL) was added n-butyl lithium (2.47M hexane solution, 0.47 mL, 1.16 mmol) at −78° C. under nitrogen atmosphere, then, the solution was stirred for 1.5 hours on an ice bath. The solution was cooled again to −78° C., N,N-dimethylformamide (487 μl, 4.84 mmol) was added, and the solution was stirred for 45 minutes while warming to room temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, then, filtered with silica gel, the filtrate was concentrated in vacuo, and 5-benzyloxy-thiophene-2-carbaldehyde (171 mg) was obtained.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]([NH2:23])=[S:22])[N:17]=[CH:16]1>>[NH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][C:6]([O:11][CH3:12])=[CH:5][C:4]=4[C:3]=3[N:23]=2)[N:17]=[CH:16]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: COc1ccc2c(c1)C(=O)C(Br)C2
Agent: Cl
Product: COc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1C2

Procedure:
Starting compounds: 2-bromo-6-methoxy-1-indanone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5]>CO>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CO
Product: CC(C)=CCC[C@H](C)CCO
Reaction time: 5 h
Yield: 96.6 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 24.0 g (155.6 mmol) of geraniol, 122 ml of methanol and 20.8 mg (0.026 mmol) of Ru(CH3COO)2 [(R)-MeOBIPHEP] as the catalyst. The hydrogenation was effected at 20° C. and 60 bar. The conversion after 5 hours amounted to 99.9%. The hydrogenation solution was evaporated at 45° C./17 mbar and the crude product was distilled at 60°-65° C./0.03 mbar. There were obtained 23.5 g of (S)-citronellol as a colourless oil; e.e. 98.8%.