Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Reactant: c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccccc2)c2ccccc2)cc1
Yield: 25.2 %

Procedure:
In all embodiment, the starting material 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 2.50 mmol) and benzene (1430 mg, 18.31 mmol) are placed in a round bottom flask and then dissolved in 10 ml of dichloromethane. Subsequently, trifluoromethanesulfonic acid (0.09 ml, 1.10 mmol) is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 140° C., the crude product is extracted with 50 ml of Ethyl acetate and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 281 mg of 10,11,11-triphenyl-11H-indeno[1,2-b]quinoline. The percentage yield is 91.7%.
Reaction SMILES: C=O.[CH2:3]([C:5]([N+:20]([O-:22])=[O:21])(CN1CCOCC1)[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:4]>>[N+:20]([CH:5]([CH2:3][CH3:4])[CH2:6][N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)([O-:22])=[O:21]
Reactant: CCC(CN1CCOCC1)(CN1CCOCC1)[N+](=O)[O-]
Agent: C=O
Product: CCC(CN1CCOCC1)[N+](=O)[O-]

Procedure:
Formaldehyde, 37%, is added to the vessel with constant agitation and maintaining the temperature within the preferred 55°-60° C. range. The formaldehyde is added over a 21/2-6 hour addition period. Preferably, the formaldehyde is added in about 3-4 hours addition time. Addition times of less than 21/2 hours produce, 4,4'-(2-ethyl-2-nitrotrimethylene)dimorpholine and addition times of longer than 6 hours have no appreciable effect on product formation. Longer addition times than 6 hours and interruptions during addition produce no deleterious effects on the product quality or yield of the 2-nitrobutylmorpholine. The reaction mixture is held at the preferred temperature for a combined addition and holding period of 41/2-8 hours. Preferably, the reaction mixture is held for a minimum of two hours after the addition of the formaldehyde. During the holding period, the reaction goes to completion and any of the dimorpholine product formed converts to 2-nitrobutylmorpholine.
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH3:14])[CH:5]=[C:4](OC)[C:3]=1[C:17](=[O:19])C>C(O)C>[CH:17](=[O:19])[C:3]1[CH:2]=[CH:7][C:6]([O:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COc1ccc(C=O)cc1

Procedure:
In 80 ml of ethanol were dissolved 13.76 g of the 2'-hydroxy-4',6'-dimethoxy-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 14 and 7.5 ml of p-anisaldehyde, and the solution was cooled to 0° C. and 120 ml of a saturated ethanol solution of potassium hydroxide was added to the solution. The mixture was stirred for 38 hours. After the reaction, the reaction liquid was diluted with water and neutralized with 6N hydrochloric acid, and the precipitated crystal was recovered by filtration, washed with water, dried and recrystallized from methanol to obtain 16.20 g (yield=81.4%) of 2'-hydroxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow needle.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:5]=[C:6]([I:8])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[I:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]2=[O:16])[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: O=C(O)CCCC(=O)Nc1cc(I)cc(I)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(=O)N1c1cc(I)cc(I)c1
Reaction time: 1 h

Procedure:
A mixture comprising 23.0 g. of N-(3,5-diiodophenyl) glutaric acid monoamide, 50 g. of acetic anhydride and 1 g. of anhydrous sodium acetate was fed to a 100 ml. four-necked flask and heated with stirring at 80° - 90° C. for 1 hour. Thereafter, the acetic acid and acetic anhydride were removed by distillation under reduced pressure, and the residue was washed with water and then dried to obtain 21.2 g. of the above-mentioned compound in the form of white crystals, m.p. 177° - 178.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33]Br)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCN3CCN(C)CC3)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 33.5 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-bromopropoxy)phenyl]benzamide (520 mg) in N,N-dimethylformamide (15 ml) was added potassium carbonate (386 mg) and 1-methylpiperazine (280 mg) at ambient temperature. The reaction mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with water, saturated sodium hydrogen carbonate and brine. The organic solution was dried over sodium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 30 g, 10% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl]benzamide (180 mg).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([OH:22])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:48][CH:49]1[C:58](=[O:59])[C:57]2[C:52](=[CH:53][C:54]([Br:60])=[CH:55][CH:56]=2)[O:51][CH2:50]1.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:60][C:54]1[CH:53]=[C:52]2[C:57]([C:58](=[O:59])[CH:49]([NH:48][C:20]([C@@H:16]3[CH2:17][CH2:18][CH2:19][N:15]3[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])=[O:22])[CH2:50][O:51]2)=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1COc2cc(Br)ccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1COc2cc(Br)ccc2C1=O
Yield: 82.6 %

Procedure:
N-Methylmorpholine (2.14 mL, 19.4 mmol) was added to a mixture of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.93 g, 8.98 mmol) and 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.41 g, 8.98 mmol), in N,N-dimethylformamide (6 mL). After 5 min solution of 3-amino-7-bromochroman-4-one hydrochloride (2.5 g, 8.9 mmol) and N-methylmorpholine (2.14 mL, 19.4 mmol) in N,N-dimethylformamide (6 mL) was added. After 1 hour the mixture was diluted with ethyl acetate (100 mL) and was with water (2×25 mL), saturated sodium bicarbonate (25 mL), saturated ammonium chloride (25 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluant of (10% methanol in ethylacetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (2S)-tert-butyl 2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate (3.23 g, 7.35 mmol, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:34](=O)[CH2:35][CH3:36].[BH3-]C#N.[Na+].Cl>CO.O.CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][CH3:36])[CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4CCCNC4)cc23)ccc1Oc1ccccc1
Reactant: CCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCN1CCCC(C#Cc2ccc3ncnc(Nc4ccc(Oc5ccccc5)c(C)c4)c3c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine (114 mg, 0.2 mmol) and propionaldehyde (116 mg, 2.0 mmol) were dissolved in MeOH/H2O (5/0.5 mL) and the pH was adjusted to 5 with AcOH. The reaction was stirred at room temperature overnight and followed by the addition of NaBH3CN (13 mg, 0.2 mmol) over a period of 1 hour. After stirring for another hour, the reaction was concentrated and the residue was partitioned between CH2Cl2 (30 mL) and saturated Na2CO3 (20 mL). The separated organic layer was dried over sodium sulfate and concentrated. Purification by preparative TLC using 10% MeOH in EtOAc gave the free base product which was converted to HCl salt to yield 42 mg (38%) of yellow solid: 1H NMR (CD3OD) δ 1.03 (t, 3H), 1.78-1.87 (m, 4H), 2.01-2.08 (m, 2H), 2.28 (s, 3H), 2.96 (t, 1H), 3.07-3.19 (m, 3H), 3.31 (br, 1H), 3.59 (d, 1H), 3.80 (d, 1H), 6.94 (m, 3H), 7.09 (t, 1H), 7.34 (t, 2H), 7.53 (d, 1H), 7.63 (s, 1H), 7.80 (d, 1H), 8.05 (dd, 1H), 8.73 (s, 1H), 8.75 (s, 1H); MS m/z (MH+) 477.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][CH2:20][CH2:21]Br)(=[O:18])[CH3:17]>CN(C=O)C>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH3:21]
Reactant: Cc1cc(Br)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.7 %

Procedure:
A mixture of 4-bromo-2-methylphenol (10.0 g, 53.5 mmol) and 325 mesh potassium carbonate (11.08 g, 80.2 mmol) in DMF (100 mL) is treated dropwise with bromoethyl acetate (10.71 g, 64.1 mmol) and then stirred for about 20 hours at room temperature under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford about 15.01 g (100%) of the titled compound. Rf=0.33 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1>CO>[CH:19]1([CH2:22][NH:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([O:5][C:4]3[CH:15]=[CH:16][C:17]([F:18])=[C:2]([F:1])[CH:3]=3)[CH2:11][CH2:10]2)[CH2:21][CH2:20]1
Reactant: NCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Reactant: O=CC1CC1
Solvent: CO
Product: Fc1ccc(OC2CCN(CCNCC3CC3)CC2)cc1F
Reaction time: 4 h

Procedure:
The product of Step d (0.4 g) dissolved in MeOH (6 ml) was added to cyclopropanecarbaldehyde (0.116 ml) and the resulting mixture was stirred for 4 hours. The solvent was evaporated, the residue re-dissolved in methanol (6 ml) and NaBH4 (0.095 g) added and the mixture left for 30 minutes. Aqueous sodium hydroxide (1N) was added and the aqueous extracted with diethyl ether. The organic extracts were dried with Na2SO4, filtered and concentrated to give the sub-title product as an oil (0.493 g).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[C@@:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)([CH3:13])[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)(C)(C)C.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O.[OH-].[Na+].C(O)(C(F)(F)F)=O>CS(C)=O>[CH2:21]([N:10]1[CH2:11][C@:12]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([CH3:13])[C@H:8]([NH:7][CH3:6])[CH2:9]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@@]1(C)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@@]1(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g (4.99 mmol) rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-4-methyl-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 0.67 g (5.99 mmol) potassium tert.-butoxide and 0.786 (6.24 mmol) dimethyl sulfate in 40 mL DMSO was stirred for 1 h at room temperature. The mixture was poured on ice-water containing NaOH (1N) and extracted with TBME. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated. The residue was dissolved in 30 mL DCM, 5.69 g (49.9 mmol) TFA was added and the mixture was stirred at room temperature for 15 h. Ice-water was added and the pH was adjusted to 12 with NaOH aq. and stirred for 15 min The organic layer was separated and washed with brine and the aqueous layer was extracted with DCM. The combined organic layers were dried with Na2SO4, filtered and evaporated. The residue was taken up on isolute and subjected to purification by chromatography on silica eluting with a gradient formed from DCM, methanol and NEt3 to yield after evaporation of the product containing fractions 0.83 g (53%) of the title compound as light yellow oil. MS m/e: 315.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([N:20]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([NH:29][O:30]C5CCCCO5)=[O:28])=[CH:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Cl>CO>[OH:30][NH:29][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][N:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1
Reactant: Cn1ccc2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccc21
Agent: Cl
Solvent: CO
Product: Cn1ccc2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NO)c4)cc3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.346 g (E)-3-{1-[4-(1-methyl-1H-indol-5-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 20 ml methanol and 13.9 ml 0.5M aqueous HCl is stirred at ambient temperature for 24 h. The crude product is isolated and in case of incomplete deprotection the resulted mixture is treated again with 1N aqueous HCl until the reaction is at completion. The crude product is isolated by evaporation and the title compound is isolated by prep-HPLC chromatography using an ammonium formiate gradient. By this method 0.047 g of the title compound are obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15](OS(C)(=O)=O)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Si](C)(C)C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1Cl>[C:1]([N:9]1[CH2:16][C@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1

Procedure:
A suspension of powdered (cis)-1-benzoyl-4-mesyloxy-L-proline (250 mg, 0.8 mmole) in 1,2-dichlorobenzene (3 ml) was stirred under argon and treated with phenyltrimethylsilane (1 ml, 5.8 mmole) followed by aluminum trichloride (383 mg, 2.87 mmole). The reaction was stirred overnight and an aliquot was removed, quenched into 1N HCl and extracted with ethyl acetate. Analysis of the organic layer by tlc showed the presence of:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1nnc(N)s1
Product: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
By the procedure of Example 8(i), 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole (from the dihydrobromide) is reacted with 1-nitro-2,2-bis-methylthioethylene to give 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)-methylthio)ethylamino]ethylene.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:9].[ClH:23]>CC(O)C>[ClH:23].[O:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NCC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tert-butylamine (15 ml) was added with stirring to a solution of 2-bromo-4'-phenoxyacetophenone (12.7 g, prepared by bromination of 4'-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture heated at 80° C. for 3 hours. The mixture was cooled to 0° C. and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4'-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26](Br)[CH3:27].[H-].[Na+]>>[CH2:26]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[CH3:27]
Reactant: CCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CCN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), ethyl bromide and sodium hydride, to give the desired product as a colorless oil (76%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.Br[CH2:40][CH2:41][F:42].[H-].[Na+].[Br-].FC(F)(F)C(O)=O>CN(C=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:40][CH2:41][F:42])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C@:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: FCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)C1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg (0.11 mmol) of amine 7-2 in DMF at 0° C. was added 13 μL (0.17 mmol) of 1-bromo-2-fluoroethane and 8 mg (0.17 mmol) of NaH (60% dispersion in oil). After warming to room temperature, another portion of NaH and the bromide were added, and the reaction was allowed to stir overnight. LC-MS indicated still 25% unreacted 7-2, so the mixture was heated to 60° C. for several hours. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and 15% aqueous Na2CO3, the layers were separated, the organic phase was washed with saturated NaHCO3, water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 12-1 as a white solid. Data for 12-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6-4.4 (m, 4H), 4.0 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.9 (s, 3H), 2.75-2.65 (m, 2H), 2.2 (m, 2H), 1.9 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H30F3N3O2: 474.2363. Found: 474.2355. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 150 ml/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 30% isopropanol in hexanes (with 0.1% diethylamine) at 1 ml/min indicated that inactive enantiomer has Rt=6.3 min and the active enantiomer has Rt=7.5 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH3:38][C:39]1[N:47]=[C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:41]([C:40]2[C:39]([CH3:38])=[N:47][C:46]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=3)=[CH:45][CH:44]=2)=[O:42])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.