Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCCC1
Temperature: 0 °C

Procedure:
30 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 150 ml piperidine. The temperature of the reaction was allowed to rise during the addition. After the addition was complete, the reaction was heated at reflux temperature for two hours. The hot reaction mixture was poured into ice water, made acid by the addition of concentrated HCl until precipitation of the product was complete and filtered. The filter cake was recrystallized from ethanol to give 30.4 grams 5-nitro-2-piperidinobenzoic acid. m.p. = 201°-203° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-piperidinobenzoic acid. m.p. = 232°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl.O>[N:18]1([C:24]([O:10][C:8]2[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[C:6]([F:11])[CH:7]=2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1c(F)cc(OC(=O)N2CCOCC2)cc1F
Yield: 93.8 %

Procedure:
To a 250 mL dry round bottom flask were added 2,6-difluoro-4-hydroxybenzaldehyde (5.53 g, 35.0 mmol), anhydrous CH2Cl2 (40 mL) and pyridine (3.68 mL, 45.5 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.4 mL, 37.4 mmol) was added. After stirring at 0° C. for 1 hour, the mixture was stirred at room temperature overnight. Water (80 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl morpholine-4-carboxylate (8.90 g) as white solid. Yield: 94%. 1H NMR (CDCl3, 300 MHz): δ=10.28 (s, 1H), 6.91 (dd, J=10.8, 1.5 Hz, 2H), 3.77-3.58 (m, 8H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=183.7, 163.8 (dd, J=263.1, 8.53 Hz), 157.0 (t, J=15.3 Hz), 151.8, 111.7 (t, J=11.5 Hz), 106.6 (dd, J=25.1, 3.70 Hz), 66.6, 66.5, 45.2, 44.5.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]([NH:15][CH3:16])[N:4]=1.CS(O)(=O)=O.[H][H]>[Pd].C.CO>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([NH:15][CH3:16])=[C:6]([NH2:12])[CH:7]=1
Reactant: [H][H]
Reactant: CNc1nc(NC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: CNc1nc(NC)c(N)cc1N

Procedure:
A 250 ml Parr bottle was charged with 2,6-di(methylamino)-3,5-dinitropyridine (20.0 g, 0.088 mole), 30 ml methanesulfonic acid, 200 ml methanol and 1.0 g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 65 psig. When no further uptake of hydrogen was observed, the mixture was treated with anhydrous silica gel (25 g), filtered free of catalyst and drying agent under a nitrogen atmosphere, and methanol removed under vacuum. The trimethanesulfonate salt of 3,5-diamino-2,6-di(methylamino)pyridine was obtained under nitrogen by addition of cold i-butanol-benzene to the concentrate, followed by vacuum drying (40°-50°C) over P2O5.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>>[CH2:1]([C:8]1[C:19]2[CH2:20][O:21][CH2:22][C:23]=2[C:10]([OH:9])=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1coc(Cc2ccccc2)n1
Reactant: CS(=O)(=O)C1=CCOC1
Product: CCc1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
9.4 g (50 millimoles) of 2-benzyl-4-ethyloxazole and 29.6 g. (200 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated for 15 hours at 150°. Unconverted sulfone is distilled off in a high vacuum. The residue is digested in methylene chloride, the undissolved constituent is filtered off, and the filtrate is extracted with 150 ml of 10% strength sodium hydroxide solution. The alkaline solution is neutralized and extracted with methylene chloride. On concentrating the methylene chloride solution, 6.2 g of 4-benzyl-6-ethyl-1,3-dihydro-furo[3,4-c]pyridine-7-ol remain. Melting point, after recrystallization from nitromethane: 148° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]>COC(OC)N(C)C>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[N:27]=[CH:6][N:7]([CH3:13])[CH3:8])=[CH:22][C:21]=2[CH3:29])=[CH:18][CH:19]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(N)=O)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc1
Agent: COC(OC)N(C)C
Product: Cc1cc(C(=O)N=CN(C)C)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
(4′-Carbamoyl-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-4-b: 200.0 mg, 0.487 mmol) was dissolved in dimethylformamide dimethylacetal (5.0 ml) and heated to 120° C. After 2 hours, the reaction mixture was cooled to room temperature and the volatiles removed under reduced pressure. The resulting residue was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.[C:29]([N:33]1[CH2:38][CH2:37][C:36](=[CH:39][Sn](C)(C)C)[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([N:33]1[CH2:38][CH2:37][C:36](=[CH:39][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[N:3]=2)[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N1CCC(=C[Sn](C)(C)C)CC1
Reactant: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Product: CC(C)(C)N1CCC(=Cc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccc(F)cc3Cl)n2)CC1

Procedure:
The 7-[(1-tert-butylpiperidin-4-ylidene)methyl]-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one was prepared from 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND CCC1) and 1-tert-butyl-4-[(trimethylstannyl)methylene]piperidine (INTERMEDIATE ABA3) by a procedure analogous to that described in EXAMPLE CZC1. Mass spectrum (ESI) 570 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:28][C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19])([CH3:26])[CH3:27]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 20 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, and the precipitate which appears is filtered out and rinsed with ethyl acetate. After the solution is concentrated under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered out. The solvent is eliminated under vacuum and the residue is precipitated from diethyl ether. The solid is recovered by filtration, rinsed abundantly with diethyl ether in order to produce a white powder with a yield of 65%. Melting point: 277-278° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:17][C:18]1[C:26](O)=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CN(C=O)C.C1(C)C=CC=CC=1.O>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[O:9][C:26]3[C:18](=[C:19]([C:20]([OH:22])=[O:21])[CH:23]=[CH:24][CH:25]=3)[N:17]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C1CCOCC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc2oc(C3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To an ice-cold suspension of tetrahydro-2H-pyran-4-carboxylic acid (0.65 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.47 mL, 5.0 mmol) dropwise followed by a few drops of anhydrous DMF. After the ice-water bath was removed, the mixture was stirred for 1 h. To the above solution was added 2-amino-3-hydroxybenzoic acid hydrobromide (1.17 g, 5.0 mmol) followed by triethylamine (2.09 mL, 15.0 mmol). The resulting reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with 1 N HCl (20 mL) and extracted with dichloromethane. The aqueous phase was further extracted with dichloromethane (2×200 mL). The combined organic phase was washed with water (2×100 mL), dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (1.42 g, 7.46 mmol). The reaction mixture was then heated to reflux under nitrogen for 10 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (2×250 mL). The organic phase was separated, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford the 2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxylic acid (590 mg, 49%) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) δ 12.90 (br s, 1H), 7.93 (dd, J=7.9, 1.0 Hz, 1H), 7.86 (dd, J=7.9, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 3.97-3.92 (m, 2H), 3.55-3.48 (m, 2H), 3.38-3.30 (m, 1H), 2.07-2.02 (m, 2H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 248 (M+H).
Reaction SMILES: S(=O)(=O)(O)N.P([O-])(O)(O)=O.[Na+].[CH3:12][C:13]([C:16]1[CH:17]=[CH:18][C:19]([OH:24])=[C:20]([CH:23]=1)[CH:21]=[O:22])([CH3:15])[CH3:14].Cl([O-])=[O:26].[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH3:15][C:13]([C:16]1[CH:23]=[C:20]([C:21]([OH:26])=[O:22])[C:19]([OH:24])=[CH:18][CH:17]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
Sulfamic acid (1.76 g, 18.1 mmol) and sodium dihydrogenphosphate (7.33 g, 47 mmol) were added to a solution of 5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in 1,4-dioxane (100 mL) and water (40 mL). A solution of sodium chlorite (1.76 g, 15.5 mmol) in water (10 mL) was added to the mixture under ice cooling, and it was stirred for 1 hour. Then, sodium sulfite (1.80 g, 14.3 mmol) was added to the mixture, and it was stirred for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture, and pH was adjusted to 1. The residue obtained by evaporation of 1,4-dioxane under reduced pressure was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound (1.81 g, 77.4%) as a white powder.
Reaction SMILES: C(OC(=O)[CH:7]([C:11](=[O:24])[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:13]=1[Cl:23])[C:8]([CH3:10])=[O:9])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:23][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]([CH2:7][C:8](=[O:9])[CH3:10])=[O:24]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)C(C(C)=O)C(=O)OC(C)(C)C)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C(=O)CC(C)=O)c1Cl

Procedure:
A suspension of 1.65 g of magnesium ethylate in 30 ml of toluene was kept at 60-70° C. and 2.28 g of acetoacetic tert-butyl ester was added dropwise thereto. After the dropwise addition was completed, the resultant mixture was refluxed for two hours. Then, the reaction solution was cooled to room temperature and 3.85 g of 2,6-dichloro-3-methoxycarbonyl benzoic acid chloride was added dropwise thereto. The reaction mixture was stirred at room temperature for two hours and at 50-100° C. for three hours, then cooled to room temperature, treated with dilute hydrochloric acid, and extracted from ethyl acetate. Then, the organic layer was alkali extracted from an aqueous 5% sodium carbonate solution. The water layer was mixed with chloroform, educed with dilute hydrochloric acid, and extracted again. The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.80 g of 2-(2,6-dichloro-3-methoxycarbonyl benzoyl) acetoacetic tert-butyl ester. A solution of this ester in 45 ml of toluene and 0.2 g of p-toluene sulfonic acid hydrate added thereto were refluxed together for six hours. The reaction solution was cooled, mixed with 200 ml of ethyl acetate, washed twice with 200 ml of water, further washed with saturated saline solution, and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone. nD22 1.5759.
Reaction SMILES: [CH2:1]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]([C@:17]1([OH:27])[CH:16]=[CH:15][C@@H:14]2[C@@:19]34[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]2[CH2:12][C:11]2[C:20]3=[C:21]([O:22][C@@H:18]14)[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:9][CH:10]=2)(=[O:38])[CH3:37]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3CC4=CCC(O)(Cc5ccccc5)C5=C4[C@@]2(CCN3C)[C@H]1O5
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH2Cl2 (300 ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride (7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). The reaction mixture was heated under reflux for 2 hr, cooled with an ice--H2O bath, then transferred to a separatory funnel, and washed with cold 10% aqueous NaHCO3 solution (3×100 ml). The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave 6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(v, cm-1): 2900 (m, sharp), 1727 (s, sharp, AcO); NMR (δH)(CDCl3): 7.47-7.20 (5, m, --C6H5), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2,1-H), 5.63 (1, dm, J, 10.1, 7-H), 5.43 (1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15 (1, m, 6-H), 5.14 (2, s, --OCH2Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J, 6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-Hβ), 2.79-2.70 (1, m, 14-H), 2.59(1, dd, J, 12.1 & 3.4, 16-He), 2.43 (3, s, N--CH3), 2.37 (1, td, J, 11.8 & 3.6, 16-Ha), 2.27 (1, dd, J, 18.8 & 6.6, 10-Hα), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-Ha), 1.86 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:23]([CH:24]=[CH2:25])=[CH:22][N:21]=[C:20]([CH3:26])[CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([CH3:26])=[CH:19][C:18]=3[C:17]([F:28])([F:16])[F:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(F)(F)F)c(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>[Br:16][CH2:9][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=Cc1ccccc1)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC(=Cc1ccccc1)c1ccccc1
Yield: 95.9 %

Procedure:
A mixture of 1,2-diphenyl-1-propene (9.7 g, 50 mmol), N-bromosuccinimide (8.9 g, 50 mmol), dibenzoylperoxide (0.1 g) and tetrachloromethane (50 ml) was heated at reflux for 21 h. The mixture was filtered cold and the solvent evaporated from the filtrate in vacuo to give 13.1 g of 3-bromo-1,2-diphenyl-1-propene as an E/Z isomeric mixture.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[C:4]([F:12])[C:3]=1[F:13].C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:13][C:3]1[C:4]([F:12])=[C:5]([C:21]2[S:20][CH:19]=[CH:23][CH:22]=2)[C:6]2[C:7]([C:2]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[N:8][S:9][N:10]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Fc1c(F)c(Br)c2nsnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1c(F)c(-c2cccs2)c2nsnc2c1-c1cccs1
Temperature: 105 °C
Yield: 82 %

Procedure:
4,7-Dibromo-5,6-difluoro-benzo[1,2,5]thiadiazole (0.29 g, 1 mmol), tributyl-thiophen-2-yl-stannane (0.86 g, 2.3 mmol), and Pd(PPh3)4 (20 mg) were combined into a 50-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 20 mL anhydrous toluene was added. The mixture was heated at 105° C. for 4 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with toluene/hexane (v/v, 1/2) as the eluent and recrystallization from a hexane/iso-propoanol mixture. The final product (0.276 g, 93.0% yield) was obtained as red needle crystals after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.33 (d×d, 2H, J=4.0 Hz×1.0 Hz), δ 7.66 (d×d, 2H, J=5.5 Hz×1.0 Hz), δ 7.30 (d×d, 2H, J=5.5 Hz×4.0 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[CH:13][C:12]([Cl:27])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:25])([F:24])[F:26])=[CH:13][C:12]([Cl:27])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(C)(=O)=O)nc2ccc(Cl)cc2c1Cc1ccccc1C(F)(F)F
Reactant: C1CCNCC1
Product: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 29 step D from crude 6-chloro-2-methanesulfonyloxy-4-(2-trifluoromethyl-benzyl)-quinoline-3-carboxylic acid ethyl ester (prepared in analogy to example 29 step C) and piperidine. Off white solid. MS (ESI): 477 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH2:16][NH:17][C:18](=[O:22])[CH:19]([CH3:21])[OH:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])=[CH:8][C:9]=1[CH2:16][NH:17][C:18](=[O:22])[CH:19]([CH3:21])[OH:20]
Reactant: CC(O)C(=O)NCc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)C(=O)NCc1cc(C(=O)OC(C)(C)C)ccc1N
Reaction time: 4 h

Procedure:
To a solution of t-butyl-4-nitro-3-[(2-hydroxy-N-methylacetylamino)methyl]benzoate (7.92 g, 23.15 mmole) in CH3OH (25 mL) and EtOAc (25 mL) in a Parr hydrogenation flask was added 10% Pd/C (0.20 g). The contents were shaken on a Parr shaker under H2 (50 psi) for 4 hours. The suspension was filtered through celite, concentrated under vacuum and washed with Et2O to afford the title compound as a light orange foam which was used without further purification: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)[N:3]=1.C(N(CC)CC)C>[OH-].[OH-].[Pd+2].CN(C=O)C>[C:8]([C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])=[CH:5][C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20][CH2:19]2)=[N:3][CH:2]=1)#[N:9]
Reactant: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)nc(Cl)c1C#N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1C#N
Temperature: 25 °C
Reaction time: 25.5 h
Yield: 97 %

Procedure:
A 300-mL Parr bottle charged with crude 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine (19.86 g, 52.29 mmol), 10.9 mL (7.94 g, 78.4 mmol, 1.50 equiv) of triethylamine, 220 mg Pd(OH)2 or 1.62 g (1.57 mmol, 3.0 mol %) of 20% palladium hydroxide on carbon [Pearlman's catalyst, 32.2% LOD] and 100 mL of dry DMF. The mixture was stirred at 25° C. and 48.9–43.2 psi of H2 for 25.5 hours. The pressure was vented, and the mixture was filtered through a 5.0 g pad of cellulose. The cellulose pad was washed with 10 mL of DMF. Water (400 mL) was added to the filtrate and the resulting mixture was stirred for 30 minutes. The precipitate was filtered, washed several times with H2O, and dried to afford 17.52 g (97.0%) of 5-cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thiomorphlin-4-yl)pyridine as a slightly grey solid (97% conversion).