Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([CH:16]=O)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)(=[O:3])[CH3:2].CN(C[CH2:23][O:24][C:25](=[O:39])[C@H:26]([CH:28](C)[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:27])C>C1(OC)C=CC=CC=1>[CH3:2][C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([C:16]3[N:27]=[C:26]([C:25]([O:24][CH3:23])=[O:39])[CH:28]=[C:29]4[C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[NH:31][C:30]=34)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)=[O:3]
Reactant: CC(c1c[nH]c2ccccc12)[C@H](N)C(=O)OCCN(C)C
Reactant: CC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Solvent: COc1ccccc1
Product: COC(=O)c1cc2c([nH]c3ccccc32)c(-c2ccc3c(n2)C(=O)C(NC(C)=O)=CC3=O)n1
Temperature: 100 °C

Procedure:
7-N-Acetyllavendamycin N-N-Dimethylaminoethyl Ester (Compound 19. Table l): 7-Acetamido-2-formylquinoline-5,8-dione (23) (prepared as described in Example 23) (317 mg, 0.13 mmol) was dissolved in 16 ml of dry anisole and heated to 80° C. b-methyltryptophan N,N-dimethylaminoethyl ester (41) (prepared as described in Example 41) (37.5 mg, 0.13 mmol) was added with stirring, and the stirred mixture was heated at 100° C. for 5.5 hr. The reaction mixture was allowed to cool to room temperature and the solid was filtered. The filtrate was distilled under vacuum to dryness. Ethyl acetate (3 ml) was added, and the mixture was stirred. Upon filtration 24.5 mg (a yield of 36%) of an orange solid was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([NH2:26])[CH2:17][CH2:16][CH2:15][C:14]3[N:13]=[C:12]([O:18]CC4C=CC=CC=4)[CH:11]=[CH:10][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.[ClH:31].[H][H]>C(O)C.[Pd]>[ClH:31].[NH2:26][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:18])[CH:11]=[CH:10][C:9]1=2
Reactant: NC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: NC1(Cc2ccccc2)CCCc2[nH]c(=O)ccc21
Yield: 28 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-(phenylmethyl)-2-(phenylmethoxy)-5-quinolinamine (19.1 g) and 10% palladium-on-carbon (1.5 g) in ethanol (1 l) was acidified to about pH 2-3 with 2-propanol/hydrochloric acid solution. The mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was removed by filtration, the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was triturated with a mixture of methanol and ethyl acetate. The precipitate was collected and recrystallized form water/methanol/ethyl acetate to afford 4.6 g (28%) of product, mp 235°-238° C. (dec), in two crops.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([N:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(S(=O)(=O)N(C)c2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reaction time: 2 h
Yield: 6.8 %

Procedure:
Anhydrous potassium carbonate (0.204 g, 14.8 mmol), and methyl iodide (0.209 g, 14.8 mmol) were added to a stirred solution of 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (0.250 g, 5.94 mmol) in acetonitrile (10 mL) under a nitrogen atmosphere at room temperature. After 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude reaction mixture was subjected to purification by column chromatography on silica gel. Elution with an ethyl acetate-hexane mixture (20:80) gave 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-N-(methyl)benzenesulfonamide (0.175 g) as a white colored solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)=[O:6].[H][H].CO>O.[Pd]>[NH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH2:15][CH2:14]3)=[O:6]
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CCN)C2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)CCN)C2
Yield: 73.5 %

Procedure:
A hydrochloric acid salt of 2-(β-Alanylaminomethyl)-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.10 g, 3.26 mmol) was dissolved in water (50 ml). To the obtained solution, 10% palladium-on-carbon (1.10 g) was added, followed by stirring at 80° C. for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol to obtain 727 mg of the title compound as colorless powdery crystals (66.1%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:4]([C:3]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:2]=1[C:21]1[C:16]([O:15][CH3:14])=[CH:17][CH:18]=[C:19]([CH2:22][C:23]#[N:24])[CH:20]=1)=[O:5]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc(CC#N)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(CC#N)cc1-c1ccc(C(F)(F)F)cc1C=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
A mixture of 179.5 g (0.72 mol) of 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester in 880 g of ethanol 95% was stirred at 20-30° C. for 40 minutes and then treated with 78.5 g of solid sodium hydroxide. The resulting mixture was stirred for 5 h at 20-30° C. Ethanol was removed in vacuum at 45-50° C. and the residue was subsequently treated with 500 g of water at 20-30° C. to afford a clear solution. The solution was stirred for 40 minutes and filtered. To the filtrate was added 235 g of methyl tert-butyl ether and 600 g of water and the resulting mixture stirred for 20 min and then stood for 20 min. The layers were separated and the aqueous layer was acidified to pH<1 with hydrochloric acid. The crystals were filtered and washed with water to provide 147 g crude wet product. The crude wet product was suspended in 680 g of toluene and the mixture was heated at 75-85° C. for 7 h. The mixture was cooled to 20-30° C. and stirred for 1 hour at this temperature. The crystals were filtered off and dried at 50-55° C. in vacuum over night to afford 137 g (86% yield) of the title acid as a white to slightly yellow solid with a purity of 99.9% (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)[CH:15]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
190.8 mg of the target compound (0.55 mmol, 67.2%) was obtained using 1-(2-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[S:15][C:14]2[NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[N:23]=[C:24]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:13]=2[CH:12]=1>C(OCC)(=O)C>[CH3:10][C:11]1[S:15][C:14]2[C:13](=[C:24]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[NH:23][C:22]3[C:17]([N:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=1.[CH:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)=Nc1ccccc1NC=2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a clear solution of 0.196 g benzoic acid in 5 ml ethyl acetate was added slowly a clear hot solution of 0.5 g olanzapine free base in 10 ml ethyl acetate. After complete addition, slowly, the crystallization process started. Stirring at room temperature was continued for 5 hours. The crystals were isolated by filtration and dried overnight at 50° C. in vacuo. Isolated yield: 0.64 gram (92%). 1H-NMR confirmed the molar ratio olanzapine: acid=1:1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(CN)c[nH]c2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reaction time: 0.33 h

Procedure:
To a solution of C-(6-methyl-1H-indol-3-yl)-methylamine (0.24 g) in dichloromethane (4 ml) was added acetic anhydride (0.14 ml) and pyridine (0.13 ml) and stirring was continued at 22° C. for 20 min. The mixture was washed with aqueous HCl (1N), the organic layer was dried and evaporated. The residue was chromatographed on silica using dichloromethane/methanol (70:1) to give the title compound as a colorless foam (0.15 g). MS: 203.1 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[CH:8][C:9]2[CH2:10][N:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:13]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)C>C(O)C.[OH-].[Na+]>[Cl:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:16]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[N:7]=[CH:8][C:9]=3[CH2:10][N:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:13]=2[CH:20]=1
Reactant: CCOC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 4.0 g (9.76 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethyl ester in 30 ml of ethanol and 25 ml of 1N sodium hydroxide was heated on the steam bath for 3 hr. The mixture was partitioned between 75 ml of water and 75 ml of ether. The basic layer was acidified with acetic acid and extracted with dichloromethane (2×100 ml), which was dried and evaporated. The resulting oil was crystallized from methanol and recrystallized from dichloromethane/ether/petroleum ether to give off-white prisms, mp 138°-140° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[OH:61])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33].Br[CH2:63][CH2:64][F:65]>>[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[O:61][CH2:63][CH2:64][F:65])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a pale yellow semi-solid. IR (liq.) 2969, 2935, 1609, 1563, 1482, 1391, 1294, 1243, 1206, 1182, 1172, 1159, 1124, 1110, 1047 cm−1; OAMS supporting ions at: ESI+ 450.0; MS (CI) m/z 450 (MH+); HRMS (FAB) calcd for C27H32FN3O2+H1 450.2556, found 450.2544. Anal. Calcd for C27H32FN3O2: C, 72.14; H, 7.17; N, 9.35. Found: C, 72.24; H, 7.20; N, 9.33.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH:1]([N:4]1[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]1=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Yield: 61.3 %

Procedure:
A solution of 7.5 g of 2-isopropylaminobenzaldehyde, 11.0 g of diethyl malonate and 11.6 g of sodium hydrogen carbonate in 80 ml of acetic anhydride was stirred at 100° C. for 15 hours. After the solvent was removed by distillation in vacuo, water was added to the residue. The mixture was then extracted with ethyl acetate. After the organic layer was washed with water and then with saturated sodium bicarbonate aqueous solution, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off in vacuum. The resulting oily substance was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain 7.3 g of ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 0 °C

Procedure:
A mixture of 5-acetylamino-6-bromo-1-indanone (36.0 g, 0.13 mol) and 6M aqueous hydrochloric acid (800 mL) was refluxed for 1 h. The homogenous solution was then cooled to 0° C. and adjusted to pH 8 with 10M aqueous NaOH (−480 mL). The precipitate formed was collected, washed with water and dried under vacuum to afford 30.0 g (quantitative) of the title compound as a light brown powder. 1H NMR (acetone-d6): δ7.65 (1H, s), 6.90 (1H, s), 5.80 (2H, br s), 2.95 (2H, t), 2.50 (2H, t).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:11]=[CH:10][C:9]=2[N+:23]([O-:25])=[O:24])=[C:4]([F:28])[CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl.[F:63][C:64]1([F:68])[CH2:67][NH:66][CH2:65]1.N#N>>[F:63][C:64]1([F:68])[CH2:67][N:66]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]3[CH:13]=[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)[CH:11]=[CH:10][C:9]=3[N+:23]([O-:25])=[O:24])=[C:4]([F:28])[CH:3]=2)[CH2:65]1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3F)c2)nc1
Reactant: FC1(F)CNC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: N#N
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(N4CC(F)(F)C4)cc3F)c2)nc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 61.1 %

Procedure:
To a sealable vial was added N-(4-bromo-2-fluorobenzyl)-5-((5-methylpyridin-2-yl)methoxy)-2-nitroaniline (700 mg, 1.57 mmol) RuPhos precatalyst (234 mg, 0.314 mmol) and RuPhos (149 mg, 0.314 mmol), 3,3-difluoroazetidine hydrochloride (610 mg, 4.71 mmol) and N2 sparged THF (7.84 mL) followed by LiHMDS (6.27 mL, 1.0 N in THF). The resulting mixture is stirred at RT for 3 min. The resulting mixture was partitioned between NH4Cl and EtOAc, the organic layer was separated, dried and concentrated to dryness. The residue was purified by FCC to provide the title compound (440 mg, 61%). MS (ESI): mass calcd. for C23H21F3N4O3, 458.16; m/z found, 459.1 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]([CH3:32])([CH3:31])[CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O.[OH-].[Na+].[PH4+]>ClCCl.O>[CH2:2]([O:4][C:5](=[O:6])[C:7]([CH3:31])([CH3:32])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:36][C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[Cl:33])[CH3:3]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCC=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
(5-Ethoxycarbonyl-5-methylhexyl)-triphenylphosphonium bromide (35.0 g, 0.0619 mol) was dissolved in dichloromethane (100 mL) containing 2-chlorobenzaldehyde (8.70 g, 0.0619 mol). A solution of sodium hydroxide (10 g, 0.25 mol) in water (10 mL) was added in portions over ten minutes. The mixture stirred for 2 hours at room temperature. After two hours, the layers were separated and the dichloromethane fraction was washed with water (2×150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining brown oil (18.99 g) was filtered through silica gel (200 g), eluting with ethyl acetate/heptane (1:9). The product containing fractions were combined and concentrated under reduced pressure. The remaining yellow oil (10.5 g) was contaminated with 2-chlorobenzaldehyde (30-40%). The material was reprocessed by dissolving in fresh dichloromethane (100 mL) with additional phosphonium salt (25 g, 0.048 mol). Sodium hydroxide (10 g, 0.25 mol) in water (10 mL) was added in portions and the mixture was allowed to stir for 4 hours at room temperature. The layers were separated and the dichloromethane fraction was washed with water (2×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining brown oil was purified by column chromatography on silica gel (200 g), eluting with ethyl acetate/heptane (1:9). The product-containing fractions were combined and concentrated under reduced pressure to provide 7-(2-chlorophenyl)-2,2-dimethylhept-6-enoic acid ethyl ester (12.0 g, 60% yield) as a light, yellow liquid. 1H NMR (300 MHz, CDCl3/TMS): δ=7.47 (d, 0.4H, J=7.5 Hz), 7.36-7.07 (m, 3.6H), 6.74 (d, 0.4H, J=15.6 Hz), 6.50 (d, 0.6H, J=11.4 Hz), 6.16 (dt, 0.4H, J=15.6, 7.2 Hz), 5.75 (dt, 0.6H, J=11.4, 7.2 Hz), 4.10 (m, 2H), 2.26-2.12 (m, 2H), 1.61-1.34 (m, 4H), 1.29-1.17 (m, 3H), 1.14 (s, 6H). (mixture of cis/trans isomers). 13C NMR (75 MHz, CDCl3/TMS): δ=177.59, 135.63 (2 peaks), 133.67, 133.45, 133.31, 132.38, 130.31, 129.41, 129.19, 127.84, 127.73, 126.57, 126.47, 126.24, 126.00, 60.16, 42.12, 42.07, 40.22, 33.56, 28.83, 25.21, 25.16, 24.69, 14.30. (mixture of cis/trans isomers). HRMS (MMI-TOF): Calculated for C22H29Cl2NO2S (MH+): 406.1202, found 406.1594.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(OC)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 226.4 %

Procedure:
A mixture of 4-bromomethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.70 g, 4.78 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.21 g, 4.78 mmol) and potassium carbonate (992 mg, 7.18 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.72 g): MS: (+) m/z 529.10 (M+H+), 551.20 (M+Na+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:18]2)[N:13]=1)C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[CH3:2][NH:3][CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:18]2)[N:13]=1
Reactant: CN(Cc1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCc1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 ml (1.73 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 96 mg (0.17 mmol) of the compound from Example 90A in 0.8 ml of dioxane, and the mixture was stirred at room temperature for 24 h. The reaction mixture was then concentrated under reduced pressure, dichloromethane was added and the mixture was concentrated again. Yield: 85 mg (99% of theory).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH3:28][O:29][CH2:30][CH:31]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:31][CH2:30][O:29][CH3:28])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: COCC=O
Agent: Cl
Product: COCCN1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with methoxy acetaldehyde in analogy to experiment L3 to give (2S,4R)-1-(2-methoxy-ethyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 446.3 [M+H]+.