Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH:20][CH2:21][CH2:22][CH3:23])[CH3:19]>CCO>[CH2:18]([N:20]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1)[CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CCCNCC
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCN(CC)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), N-ethylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 0.1), 101 (7), 100 (bp), 95 (5), 72 (14), 58 (12).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[I:12])=[CH:9]/[CH2:10]O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.BrN1C(=O)CCC1=O.Cl.[C:41]([N:45]([CH2:47][C:48]([OH:50])=[O:49])C)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[I:12])=[CH:9]/[CH2:10][N:45]([CH2:47][C:48]([OH:50])=[O:49])[CH3:41])=[CH:4][CH:3]=1
Reactant: CN(CC(=O)O)C(C)(C)C
Reactant: OC/C=C(\I)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C/C=C(\I)c1ccc(Br)cc1)CC(=O)O
Reaction time: 8 h

Procedure:
A solution of (Z)-1-(4-bromophenyl)-1-iodopropene-3-ol C (8.81 g, 26.0 mmol) in CH2Cl2 (220 mL) was chilled in a dry-ice/acetonitrile bath under argon. PPh3 (10.9 g, 41.6 mmol), and N-bromosuccinimide (NBS, 7.40 g, 41.6 mmol) were added. After 1 hour the reaction was quenched with saturated NaHCO3. The mixture was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was immediately taken up into anhydrous acetonitrile (MeCN, 104 mL). t-butyl sarcosine hydrochloride (5.20 g, 28.6 mmol), K2CO3 (35.9 g, 260 mmol), and KI (21.6 g, 130 mmol) were added. The mixture was stirred overnight, then filtered and the filter cake washed with EtOAc. The filtrate was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. Column chromatography (20% EtOAc/hexanes) provided (Z)-N-(1-(4-bromophenyl)-1-iodoprop-1-en-3-yl)sarcosine, tbutyl ester D (9.63 g, 80% over 2 steps) as a light brown oil. 1H NMR (300 MHz, CDCl3) 1.48 (s, 9H), 2.46 (s, 3H), 3.23 (s, 2H), 3.43 (d, 2H), 6.12 (t, 1H), 7.34 (d, 2H), 7.43 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: COc1cccc(N)c1C(=O)O
Product: COc1cccc(N)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 78 %

Procedure:
Starting from 2-amino-6-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (170 mg; 78% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13](F)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:36]2[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]2=[O:46])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>N1C=CC=CC=1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13]([N:33]3[CH2:34][CH2:35][N:30]([C:29]4[CH:28]=[CH:27][C:26]([N:36]5[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]5=[O:46])=[CH:25][C:24]=4[F:23])[CH2:31][CH2:32]3)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCN2C
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CCOC(=O)c1cn2c3c(c(N4CCN(c5ccc(N6C[C@H](CNC(C)=O)OC6=O)cc5F)CC4)c(F)cc3c1=O)OCN2C

Procedure:
A solution of 100 mg 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32 mmol) and 216 mg of N-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}-methyl]-acetamide (0.64 mmol) were dissolved in a mixture of 1 ml pyridine and 1 ml DMSO. The reaction was monitored by TLC. The DMSO was evaporated, the residue digested in water and the solid collected. The solid was purified by chromatography, using a 9/1 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:43])[CH:39]=1)[CH2:34]2
Reactant: N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (72 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (78 mg, 0.28 mmol) [Bell et al. WO 2006/031606], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:38]4[CH:43]=[N:42][CH:41]=[CH:40][N:39]=4)[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(c2cnccn2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (20.0 mg, 0.046 mmol) in DMF (0.5 mL) are added Cs2CO3 (30.1 mg, 0.092 mmol) and chloropyrazine (8.25 μL, 0.092 mmol). The reaction mixture is heated at 100° C. overnight, and additional Cs2CO3 (30.1 mg, 0.092 mmol) and chloropyrazine (8.25 μL, 0.092 mmol) are added. After heating at 100° C. for another 8 h, the reaction mixture is quenched with H2O (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layer is evaporated under vacuo and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H18ClF3N4O2 (M+H+) 511.1, found 511.1.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(F)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 125 mg 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.8 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 90 mg of the title compound as a pale yellow powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[O:23][B:24](OC)[O:25]C.O>C(OCC)C>[Si:15]([O:14][CH2:13][CH2:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[B:24]([OH:25])[OH:23])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexanes, 5.78 mL) was added to a solution of [2-(3-bromofuran-2-yl)-ethoxy]-tert-butyldimethylsilane (Intermediate 34, 4.01 g) in diethyl ether (130 mL) at −60° C. under nitrogen and the resultant mixture was stirred for 30 minutes. Trimethylborate (2.73 g) was then added to the mixture and it was stirred for a further 10 minutes. The reaction mixture was warmed to 0° C., water was added and the mixture was stirred for 15 minutes. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (1.23 g) as a colourless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCCCCC.[CH3:23][CH2:24][O:25][C:26]([CH3:28])=[O:27]>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]=[CH:28][C:26]([O:25][CH2:24][CH3:23])=[O:27])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stirred and nitrogen inlet was charged with NaH (60%, 10.0 g, 0.25 mol) and anhydrous THF (200 mL). To the stirred mixture was slowly added triethylphosphonoacetate (53.8 g, 0.24 mol) over 20 minutes. A solution of crude 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (40 g, 0.20 mol) in THF (75 mL) was added dropwise. The solution turned orange and the stirring was continued for 1 h until no aldehyde remained by TLC analysis [1:1 hexane/EtOAc, Rf(aldehyde)=0.6; Rf(14)=0.8]. The solution was diluted with EtOAc and brine and the layers were separated. The EtOAc layer was washed with 1M HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14 (67 g) as a yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ6.92-6.76 (m, 1H), 5.82 (d, 1H), 4.56-4.32 (m, 1H), 4.25-4.12 (m, 2H), 3.48-3.27 (m, 2H), 2.20-1.98 (m, 1H), 1.91-1.72 (m, 2H), 1.43 (s, 9H), 1.25 (t, 3H) ppm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[C:22](Cl)=[CH:21][C:20]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:19][C:18]=23)=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:31][O-:32].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([O:32][CH3:31])=[CH:21][C:20]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:19][C:18]=23)=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(Cl)cc(-c4ccc(Cl)cc4)nc23)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared by stirring 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(3-methanesulfonyl-phenyl)-amide (example 175) (46 mg) with a solution of sodium methoxide (11 mg) in methanol (1.5 mL) for 2 h at 50° C., followed by precipitation of the product by the addition of water (10 mL). Pale-yellow solid. MS (ISP) 457.5 [(M+H)+]; mp 265° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:10]1[C:5]2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:2]([Br:1])=[N:7][C:6]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)nc2c1c(Br)nn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a stirred solution of ethyl 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2 g, 6.43 mmol) in acetic acid (6 mL) was added bromine (5.14 g, 32.15 mmol) at 0° C. Resulting reaction mass was stirred at room temperature for 3 h. Reaction was monitored by TLC. On completion, reaction was quenched with ice, NaHCO3 solution was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1.2 g, 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=2[CH:12]=O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[CH3:23][O:24][CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.Cl>C1(C)C=CC=CC=1>[CH3:23][O:24][CH:25]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=1[C:8](=[O:9])[C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)c(C(=O)c2ccc([N+](=O)[O-])cc2)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC=Cc1ccc(OC)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
10 g of 2-(4-nitrobenzoyl)-4-methoxybenzaldehyde is introduced together with 18 g of (methoxymethyl)triphenylphosphonium chloride in 400 ml of toluene and mixed in portions with 5.9 g of potassium-tert-butylate while being cooled with ice. After 1 hour of stirring while being cooled with ice and a subsequent 3.5 hours of stirring at room temperature, it is mixed with 200 ml of water, weakly acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate phases are washed with saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 6.9 g of 1-methoxy-2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)ethylene as a mixture of the E- and Z-forms is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([OH:29])[CH:28]=1)[CH2:5][NH:6][C:7]([NH2:25])=[N:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][O:14][C:15]=1[CH3:16])=[O:10].Br[CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([O:29][CH2:31][CH2:32][Cl:33])[CH:28]=1)[CH2:5][NH:6]/[C:7](/[NH2:25])=[N:8]/[C:9]([C:11]1[C:12]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[N:13][O:14][C:15]=1[CH3:16])=[O:10]
Reactant: COc1ccc(-c2noc(C)c2C(=O)N=C(N)NCc2cc(O)cc(Cl)c2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccc(-c2noc(C)c2C(=O)/N=C(\N)NCc2cc(Cl)cc(OCCCl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
The compound of Example 23 (8.3 mg, 0.020 mmol), 1-bromo-2-chloroethane (14 mg, 0.1 mmol), cesium carbonate (13 mg, 0.04 mmol) and potassium iodide (4 mg, 0.024 mmol) were mixed in 1 mL of THF in an 8-mL glass vial. The vial was capped and shaken at RT overnight. The reaction mixture was filtered through Acrodisc Syringe Filter (0.45 μm). Solvent was evaporated in vacuo. The residue was purified by preparative HPLC to give 2.2 mg of the title compound. LC/MS (method A) RT 2.61, MH30 477. 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=8.2 Hz, 2 H), 7.05 (d, J=8.2 Hz, 2 H), 6.99 (s, 2 H), 6.90 (s, 1 H), 4.53 (s, 2 H), 4.26 (t, J=5.3 Hz, 2 H), 3.86 (t, J=5.3 Hz, 2 H), 3.84 (s, 3 H), 2.66 (s, 3 H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[CH:6]=1)(=O)C.[OH-].[K+]>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([O:16][CH3:17])[C:8]([C:13](=[O:15])[CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(NC(C)=O)cc(OC)c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)cc(OC)c1C(C)=O
Yield: 94.6 %

Procedure:
A mixture of (4'-acetylamino-2',6'-dimethoxyphenyl)ethanone (compound 75-1) (7.11 g, 0.03 mol) and 10% potassium hydroxide solution in ethanol is heated to reflux for 3 hours. The solvent is distilled from the reaction mixture under reduced pressure. The residue is dissolved in dichloromethane, and the solution is washed with water, dried, and concentrated. The residue is placed on a silica gel column and eluted with a mixture of ethylacetate and dichloromethane (1:1) to yield the title compound as a crystalline solid (5.54 g, 95%, m.p.=154°-155° C.).
Reaction SMILES: [Cl:1][CH2:2][C:3]1([O:13][CH2:12][CH2:11][O:10]1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[K+]>C(O)C>[Cl:1][CH2:2][C:3]1([O:10][CH2:11][CH2:12][O:13]1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC1(CCl)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Ethyl 4-chloro-3,3-ethylenedioxybutanoate (15.63 gm) was dissolved in 150 ml of ethanol, and to the solution was dropwise added 75 ml of 2N potassium hydroxide. After stirring for 1 hour at room temperature, the resultant reaction mixture was concentrated under reduced pressure. Saturated brine was added to the concentrate, followed by cooling with ice water and addition of diluted hydrochloric acid to adjust pH to 3. The deposited crystals were collected by filtration and dried to obtain 11.97 gm of 4-chloro-3,3-ethylenedioxybutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C1(N(C)C2CCCCC2)CCCCC1.Cl[CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 5-chloro-1H-indazole-7-carboxylate (15 g, 30.7 mmol) and N-cyclohexyl-N-methylcyclohexanamine (10.86 mL, 50.7 mmol) in tetrahydrofuran (100 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (8.7 mL, 49 mmol). After 5 min, the ice bath was removed and stirring continued at room temperature for 24 h. The reaction was treated with 25 mL of 2M ammonia in methanol and allowed to stir at room temperature for 20 min. The reaction was diluted with diethyl ether, washed with water, then 1M potassium bisulfate, then water, then brine, dried over magnesium sulfate, and concentrated. TLC shows a slightly less polar impurity. The product was purified by column chromatography. The column was begun with 25% ethyl acetate/n-hexane and continued with that solvent system until the less polar impurity had been removed. The polarity was then ramped to 30% ethyl acetate/n-hexane to give nearly perfect separation. All absolutely pure fractions (by TLC) were combined to give 17.6 g (93%) as an amorphous white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.18 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.44 (dd, J=8.6, 5.6 Hz, 2H), 7.03 (dd, J=8.9, 8.6 Hz, 2H), 5.77 (s, 2H), 4.33 (s, 2H), 3.80 (br, 2H), 3.63 (t, J=8.2 Hz, 2H), 3.07 (m, 2H), 2.28 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.5, 161.7 (d, J=247 Hz), 155.0, 144.4, 137.5, 131.8, 129.1 (d, J=7.7 Hz), 126.8, 125.0, 124.4, 122.7, 121.1, 115.5 (d, J=21 Hz), 82.6, 79.6, 72.7, 68.0, 40.8, 40.1 (br), 32.1, 28.5, 18.1, −1.3. Mass spec.: 618.28 (MH)+.
Reaction SMILES: O=O.[CH3:3][C:4]1([CH3:11])[C:9](=[O:10])[C:7](=[O:8])[O:6][CH2:5]1.FC(F)(F)C([O-])=O.C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:11])[C@@H:9]([OH:10])[C:7](=[O:8])[O:6][CH2:5]1
Reactant: CC1(C)COC(=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])C(F)(F)F
Agent: O=O
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@@H]1O
Reaction time: 1 h

Procedure:
A 500 ml steel autoclave was loaded in a glove box (O2 -content less than 1 ppm) with 40.0 g (0.31 mol) of ketopantolactone, 210 ml of toluene, 180.6 mg (0.389 mmol) of [Rh(COD)2 ]PF6, 254.3 mg (0.389 mmol) of POPPM and 138.3 mg (0.389 mmol) of tetrabutylammonium trifluoroacetate. The hydrogenation was carried out at a constant pressure of 40 bar of H2, at 30° C. and with intensive stirring. By virtue of the exothermic reaction the temperature rose to 58° C. A conversion of above 99% was achieved after 1 hour. After a total hydrogenation time of 2 hours the mixture was worked-up as described in Example 2. Pure (R)-pantolactone was obtained. [α]D20 =-46.6°. Optical purity 90.4%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CC1(C)CC(=O)C2=C(C1)N(C(=O)c1ccccc1)CCC2

Procedure:
7,7 Dimethyl-1,2,3,4,7,8-hexahydro-quinolin5(6H)-one was reacted with benzoyl chloride according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-benzoyl-quinolin-5(6H)-one (19) as a yellow solid.