Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=1)#[N:2].[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:30][CH2:29][C@@H:28]([NH:27][C:16]([C:14]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=1)=[O:17])[CH3:31]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccccc3CO)c2)c(C#N)c1
Reactant: C[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3ccccc3CO)c2)c(C#N)c1
Temperature: 25 °C

Procedure:
A reaction vial was charged with 2-Cyano-2″-hydroxymethyl-4-methyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (50.00 mg, 0.1456 mmol), (2S)-2-aminopropan-1-ol (13.12 mg, 0.1747 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (110.7 mg, 0.2912 mmol), N,N-diisopropylethylamine (0.06341 mL, 0.3640 mmol) and N,N-dimethylformamide (5.0 mL, 64 mmol) and the reaction stirred at room temperature over night. The reaction mixture was then purified by prep HPLC to get the compound as white solid.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CNC.C1COCC1>ClCCl.ON1C2C=CC=CC=2N=N1>[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:3]([CH3:4])[CH3:2])=[O:17]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
EDC.HCl (2.47 g, 12.88 mmol) was added to a stirred mixture of 2-amino-3-nitrobenzoic acid (2.18 g, 11.98 mmol) (Mickelson, J. Med. Chem, 39(23) 4662 (1996)), 2M dimethylamine in THF (6.45 ml, 12.9 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.74 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 18 h, washed with saturated aqueous sodium bicarbonate and the organic layer dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale orange gum (2.5 g, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][CH:12]([OH:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:14][CH2:13][CH:12]([OH:15])[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(O)CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)CNc1ncccc1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (10.0 g, 0.063 mole), DL-1-amino-2-propanol (7.1 g, 0.095 mole), and triethylamine (8.75 ml, 0.063 mole) in absolute ethanol was heated at reflux for 11/2 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and methylene chloride. The water layer was separated and extracted with methylene chloride (2×). The combined methylene chloride layers were extracted with water and dried over sodium sulfate. The filtrate was evaporated to a yellow oil. The oil was purified on a silica gel column (200 g) eluting first with methylene chloride, followed by 5%, 10%, 25% (500 ml each), and finally 50% ethyl acetate/methylene chloride. The appropriate fractions (TLC using ethyl acetate) were combined and evaporated to an oil. A sample of the oil was dried at 50°-60° C., then at 70° C. for 6 hours to give 11.9 g (96%) of a yellow oil.
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:9][C@H:8]([CH3:10])[CH2:7][CH2:6][C@H:5]1[C:11](=[O:13])[CH3:12])=O.C([C@@H:19]1[CH2:24][CH2:23][C@@H:22](C)[CH2:21][C@H:20]1OCC1C=CC=CC=1)=CC(=C)C>>[C:11]([C@@H:5]1[CH2:6][CH2:7][C@@H:8]([CH3:10])[CH2:9][C@H:4]1[O:3][CH2:1][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:13])[CH3:12]
Reactant: C=C(C)C=C[C@@H]1CC[C@@H](C)C[C@H]1OCc1ccccc1
Reactant: CC(=O)[C@@H]1CC[C@@H](C)C[C@H]1OC=O
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@H]1OCc1ccccc1

Procedure:
As shown in Table 2,9-decene acetate (12) reacted smoothly to provide the carboxylic acid 9-acetoxy nonanoic acid (12a) in 93% yield. The alcohol functionality within the molecule appeared to be tolerated well in the case of isopulegol (13) which provided a combined yield of 78% of which (1R,2R,5R)-2-acetyl-5-methyl cyclohexanol (13a) was 44% and 34% was (1R,2R,5R)-2-acetyl-5-methyl cyclohexanol formate (13b). However, in contrast, the benzyl-protected version of this alcohol (14) provided 80% of the desired ketone, (1R,2R,5R)-(2-acetyl-5-methyl cyclohexyl)benzyl ether (14a). 13b and 14a are novel products. Substituted stilbenes 15 and 16 were cleanly converted into the corresponding acid products 15a and 16a, respectively, without difficulty in 91% and 95% yields, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH:5]=[N:4][C:3]=1[Cl:27].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>COCCOC>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:6]3[N:7]4[CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:1]=[C:2]4[C:3]([Cl:27])=[N:4][CH:5]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c(N)n3)cn2)CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(Cl)c2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of compound 87a (1.60 g, 4.09 mmol), and ethyl 3-bromo-2-oxopropanoate (1.72 mL, 12.3 mmol) in DME (25 mL) was stirred at 80° C. under Argon for 3 days. After cooling to rt, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (20-60% EtOAc/heptane) to give compound 87b as a light brown solid. 1H-NMR (CDCl3; 400 MHz) δ 8.43 (d, J=2.2 Hz, 1H), 8.38 (d, J=9.0 Hz, 1H), 7.74 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.44-4.52 (m, 2H), 3.68-3.75 (m, 4H), 3.60 (d, J=5.1 Hz, 4H), 1.51 (s, 9H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(Br)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(Br)cc54)CC3)nc2N1
Yield: 22.1 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-1,4-benzoxazin-3(4H)-one (Intermediate 65) (0.57 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (120 mg, 0.67 mmol) and sodium cyanoborohydride (72 mg, 1.14 mmol) were reacted as described under Example 21 to give 65 mg (22%) product as a solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH3:18])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Solvent: CO
Product: COC(=O)c1cccc(C(=O)c2ccccc2)c1
Yield: 905.5 %

Procedure:
A stirred solution of 3-benzoylbenzoic acid (10.0 g, 44.4 mmol) and p-TSA (0.85 g, 4.39 mmol) in methanol (200 mL) was heated at 75° C. for 18 hours. The reaction mixture was allowed to cool, and the solvent evaporated at reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated at reduced pressure to afford the title compound (9.55 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[N:20]([CH3:21])[CH2:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[C:10]3=[O:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>ClCCl>[CH3:39][N:40]([CH3:44])[C:41](=[O:42])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[N:20]([CH3:21])[CH2:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[C:10]3=[O:29])=[CH:30][CH:31]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1CC=Cc2c(Cc3ccc(O)cc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3c2C=CCN3C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-hydroxybenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 7, 0.025 g, 0.060 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.012 mL, 0.090 mmol) and dimethyl carbamyl chloride (0.010 g, 0.090 mmol). After 2 h, the mixture was warmed to rt and additional dimethyl carbamyl chloride (0.019 g, 0.18 mmol) was added. After 20 h, the reaction was warmed to 35° C., and after an additional 36 h, diluted with dichloromethane and washed with water and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 489.1 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 3.24 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.41-7.38 (m, 1H), 7.14 (d, J=7.9 Hz, 2H), 7.01-6.98 (m, 2H), 4.77-4.64 (m, 2H), 4.37 (s, 2H), 3.64 (br s, 1H), 3.27 (s, 3H), 3.06 (s, 3H), 2.98 (s, 3H), 2.22-2.19 (m, 1H), 2.12-2.09 (m, 1H), 1.91 (br s, 1H), 1.82 (br s, 1H), 1.64-1.60 (m, 1H), 1.49-1.25 (m, 4H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:51]1[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=1)[CH:48]([CH3:50])[CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:56]([C:54]3[N:55]=[C:51]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:52][CH:53]=3)=[O:57])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-isobutylthiazole-4-carboxylic acid (example 72, step d) (0.08 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. and the resulting yellow solution allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.24 g.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH2:24])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1>C1COCC1>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH:24][C:43]([N:40]5[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]5)=[O:44])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Reactant: O=C(Cl)N1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc2c(c1)ncn2CCNC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (0.35 g, 0.988 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 4-hydroxypiperidine-1-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC cis and trans isomers of 1-{2-[(4-hydroxypiperidine-1-carbonyl)-amino]-ethyl}-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)amide.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:24])[CH2:13]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:24])[CH2:13][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)C[C@@H](O)c2cccc3c(C)c(C)oc23)cc1
Reactant: CCNCC
Product: CCN(CC)C[C@@H](O)c1cccc2c(C)c(C)oc12
Yield: 527.3 %

Procedure:
15 g (41.65 mmol) of (+)-2,3-dimethyl-7-(2-para-methylphenylsulphonyl-1(S)-hydroxyethyl)benzofuran and 210 ml (2.03 mol) of diethylamine are introduced into a 500 ml three-necked flask equipped with a stirrer and a reflux condenser. The solution is stirred at reflux for 16 h and the solution is concentrated. The residue is purified by successive column chromatography operations (elution solvent: 90/10 dichloromethane/methanol) and dried in a desiccator under vacuum over phosphorus pentoxide. 57.4 g of (+)-2,3-dimethyl-7-(2-diethylamino-1(S)-hydroxyethyl)benzofuran are obtained in the wax form -[α]D20 =+94.7° (c=1, methanol). The enantiomeric excess is 98.5%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Ti+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Ti+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a granular (4 to 5 mm diameter) titanium dioxide, Calsicat 20503, from the Calsicat company. After 2 h reaction time, the phenol conversion was 7.2%, whereby 0.8 g phenyl chloroformate and 11.0 g diphenyl carbonate were formed. The selectivity to carbonate esters was >99%.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:6][C:7]([O:9]C)=[O:8]>CO>[CH3:4][C:5]1([CH3:17])[CH:11]([CH:12]=[C:13]([Cl:15])[Cl:14])[O:9][C:7](=[O:8])[CH2:6]1
Reactant: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 93 %

Procedure:
To a mixed solution of 6.0 parts of sodium hydroxide, 40 parts of water and 60 parts of methanol was added dropwise under reflux 26.0 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate and, after the dropwise addition had been completed, the mixture was further stirred under reflux for 2 hours. The reaction mixture was then treated in the same manner as Reference Example 1 to obtain 19.5 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C[C@@H](N)CO
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)C[C@H](CO)Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (26 mg, 80 μmol) in 400 μL of NMP was added (R)-2-amino-4-methylpentan-1-ol (33 μL, 250 μmol) and DIPEA (17 μL, 100 μmol). The reaction solution was stirred at 100° C. for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol (12 mg, 31 μmol) as powder. ES/MS m/z 378.1 (MH+).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:11]1([C:14]2[O:15][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=O)C1CC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1coc(C2CC2)n1
Temperature: 120 °C
Yield: 50 %

Procedure:
Ethyl 4-chloroacetoacetate (20.0 g, 122.0 mmol) was added to cyclopropanecarboxamide (3.52 g, 41.5 mmol) in toluene (100 mL) and 1,4-dioxane (100 mL). The mixture was refluxed at 120° C. for 17 hours then evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 petroleum ether: EtOAc) to afford the title compound as a white solid in 50% yield, 4.00 g.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[O:26][CH3:27])=[N:6]1.[OH-].[Li+].O>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[N:6]=2)=[C:20]([O:26][CH3:27])[CH:21]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2OC)n(Cc2cccc(F)c2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)ccc1-c1nn(CC(=O)O)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
159 mg (0.39 mmol) of the compound from Example 147A in 4 ml methanol are treated with 1.57 ml of a 1 N solution of lithium hydroxide in water (1.57 mmol) and the resulting mixture is stirred overnight at RT. The methanol is removed on the rotary evaporator, the residue diluted with water and the resulting aqueous phase extracted twice with dichloromethane. These organic phases are discarded. The aqueous phase is then acidified with 1 N hydrochloric acid and extracted three times with dichloromethane. The extracts are combined, dried over magnesium sulphate, freed of solvent on the rotary evaporator and the residue dried under high vacuum. 144 mg (94% of theory) of the title compound are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:28]([Zn+])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:21])[F:23])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: [Br-]
Product: CN1c2c(cc(Cc3ccccc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a colorless oil from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45) and benzyl zinc bromide. MS (ES+): 347 (base, M+H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3[N+](=O)[O-])CC2O)CCCCC1)c1cc2ccccc2o1

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 2 of Example 1 in 50 ml of ethanol, were added 3.7 ml of 2-fluoronitrobenzene and 4.8 ml of triethylamine. The reaction mixture was refluxed overnight and concentrated. The resulting residue was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: [CH:1]([S:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[CH:1]([S:4][C:5]([CH3:12])([CH3:11])[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)SC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)SC(C)(C)C(=O)O

Procedure:
A mixture of ethyl 2-(isopropylthio)-2-methylpropionate (5.4 g, 30 mmol) and potassium hydroxide (5.0 g, 90 mmol) in ethanol is refluxed for 6 hours, cooled, and concentrated in vacuo to obtain a residue. The residue is diluted with water, washed with ether, acidified with hydrochloric acid, and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. The solid is washed with chloroform and dried under reduced pressure to give the title product as a solid, mp 51.5-52.5° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][P:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:28])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OP(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Kurumada T. et. al., loc. cit., and diphenylphosphinic chloride in a procedure otherwise similar to that for preparing the compound 101 gives an 84% yield of the compound 116 which is obtained in the form of colourless crystals; melting point: 169–173° C. (dichloromethane/hexane).