Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][CH2:18][N:19]([CH3:27])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)#[N:2].C(=O)(O)[O-:38].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:5]1[O:6][C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][CH2:18][NH:19][CH3:27])=[CH:11][CH:10]=2)=[C:3]([C:1]([NH2:2])=[O:38])[N:4]=1
Reactant: CN(CCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C#N)cc1)C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNCCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Yield: 22 %

Procedure:
A solution of tert-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04 mmol) in concentrated sulfuric acid (1 ml) was stirred at room temperature overnight. The reaction was basified by addition to sat. sodium bicarbonate and then addition of 6M NaOH (to ˜pH12). The aqueous phase was then extracted with EtOAc, the combined organic phases dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(3-(methylamino)propanamido)phenylamino)oxazole-4-carboxamide (0.0038 g, 0.009 mmol, 22%). 1H NMR (CD3OD) δ 2.64 (3H, s), 2.73 (2H, t), 3.20 (2H, masked by CD3OD peak), 7.08 (2H, t), 7.29 (2H, d), 7.45 (1H, m), 7.48 (2H, d), 8.45 (1H, br. s). LCMS (2) Rt: 2.28 min; m/z (ES+) 416.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7]I.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH3:7])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CI
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
According to Scheme 5, cesium carbonate (968 mg, 3 mmol) followed by methyl iodide (1 g, 7.1 mmol) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (121 mg, 0.79 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated and column chromatographed to give 116 mg (88%) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid. 1H NMR (360 MHz, DMSO-d6) 8.62 (s, 1H), 7.71 (s, 1H), 6.62 (s, 1H), 3.84 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:31]([CH3:39])[C:32]([O:34]C(C)(C)C)=[O:33]>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:31]([CH3:39])[C:32]([OH:34])=[O:33])=[CH:16][CH:17]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CCc1cnc(N(CCc2ccc(OC(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol and t-butyl 2-bromopropionate.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(OCC)(=O)C>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitroaniline (10.0g) and chloroacetyl chloride (15 ml) were refluxed together 1 hour, mixed with ethyl acetate and washed with water 3 times to yield 11.5 g; mp 183°-185°C.
Reaction SMILES: [H][H].C(OC([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH2:22][C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1CC(=O)CC(OCC)=O)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[CH2:28]([O:27][C:25]([CH2:24][C:23](=[O:30])[CH2:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CC(=O)CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Agent: [OH-]
Product: CCOC(=O)CC(=O)CC1Cc2ccccc2N1

Procedure:
In a similar manner to that described in Preparative Example 1(iii)′ above, a debenzylation reaction using hydrogen gas and palladium hydroxide on carbon was performed, using 1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)indoline [obtained as described in Preparative Example 5(iii)′ above] instead of (2S, 4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methoxypyrrolidine, to give the title compound as an orange oil (yield: quantitative).
Reaction SMILES: [Na].[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[S:14]1[C:18]2[C:19](C(Cl)=O)=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]1([S:2]([NH:5][C:6]([C:19]2[C:18]3[S:14][N:15]=[N:16][C:17]=3[CH:22]=[CH:21][CH:20]=2)=[O:7])(=[O:3])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After the addition of a spatula tip of 4-dimethylaminopyridine to a suspension of 4 g of the sodium salt of saccharin in 60 ml of methylene chloride, a solution of 3.9 g of benzo-1,2,3-thiadiazole-7-carboxylic acidchloride in 20 ml of methylene chloride is added dropwise at a maximum of 20° C. The mixture is stirred overnight at room temperature and thenext day the suspension is poured onto ice-water and extracted with ethyl acetate. The extracts are washed with dilute sodium hydrogen carbonate solution and water, dried and concentrated by evaporation. The residue is recrystallised from tetrahydrofuran/hexane to yield the title compound having a melting point of 173°-175° C.
Reaction SMILES: [C:1]([CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2]>C(O)C.Cl.[H][H].[OH-].[OH-].[Pd+2]>[NH2:2][CH2:1][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)c1cccc(OC)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(CN)c1cccc(OC)c1
Yield: 31.4 %

Procedure:
To a solution of ethyl 3-cyano-3-(3-methoxyphenyl)propanoate (11.9 g) in ethanol (41 ml), 12 N hydrochloric acid (3.8 ml) and 20% palladium hydroxide on carbon (2.10 g) was added, and the mixed solution was stirred in hydrogen atmosphere at room temperature for 15 hours. The solvent was removed by evaporation under reduced pressure, and resulting crude product was purified by column chromatography (neutral OH type silica gel, methanol/chloroform=2 to 9%) to give ethyl 4-amino-3-(3-methoxyphenyl)butanoate (3.80 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: N#Cc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-cyanobenzoic acid: MS (ESI): m/z 394 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].[H][H]>O.[Pd].C(O)(C)C>[CH3:17][C:16]([CH2:15][CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=2[CH:7]=1)=[O:18]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
49.44 Grams (0.154 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 12.24 g (0.149 moles) of anhydrous sodium acetate, 4 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00094 moles of palladium and 400 ml of isopropanol are put into a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2.5 atmospheres. For a period of time of 9 hours the temperature of reaction is kept at 50° C., then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is concentrated to 130 ml, diluted with 45 ml of water, heated to 60° C. and added with 18.2 g of sodium metabisulfite. The reaction mixture is kept for one hour at 60° C. and then is cooled to 0° C. The so obtained suspension is kept at 0° C. for two hours and then is filtered; the solid is washed with 60 ml of isopropanol cooled to 0° C. and then is suspended in a mixture made by 70 ml of a 10% aqueous solution of sodium hydroxide and 270 ml of toluene. The reaction mixture is stirred for one hour and half at room temperature, then is heated at 60° C. and the layers are separated. The organic phase is washed with 60 ml of water and is concentrated under vacuum at 60° C. until an oil is obtained which solidifies by cooling. The solid is dissolved at 60° C. in 40 ml of isopropanol and the resulting solution is cooled to 0° C. in two hours. The obtained suspension is kept for one hour at this temperature, filtered, washed with 10 ml of cold isopropanol and dried in oven under vacuum until constant weight. 26.3 Grams of nabumetone are obtained with a yield equal to 74.8%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N1CC[CH2:22][CH2:21]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]1[CH2:18][CH2:22][CH2:21][CH2:19]1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CN(C)C)C2=O
Product: CC(=O)Nc1ccc2c(c1)CCC(=CN1CCCC1)C2=O

Procedure:
6-Acetylamino-2-[(dimethylamino)methylidene]-1-tetralone (4.90 g, 0.017 mol) obtained in Example 41-1) was suspended in pyrrolidine (25 ml), which was refluxed with heating for 2 hours. The crystallized product was collected by filtration, washed with a mixed solution of ethyl acetate and n-hexane (1:1), to give 6-acetylamino-2-(1-pyrrolidinylmethylidene)-1-tetralone (5.03 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20]>>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][CH:27]=1)#[CH:20]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(Nc2ncnc3sc4c(c23)CN(C(=O)OCC)C4)c1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (235 mg, 0.83 mmol) and 3-ethynylaniline (102 mg, 0.87 mmol) were reacted to the title compound to yield 211 mg (67%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:20])[CH2:18][NH:17][C:16](=[O:19])[CH2:15]1>>[CH3:13][C:14]1([CH3:20])[CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:16](=[O:19])[CH2:15]1
Reactant: CC1(C)CNC(=O)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(N2CC(C)(C)CC2=O)cc1
Yield: 103.1 %

Procedure:
Using ethyl 4-iodobenzoate (552 mg) and 4,4-dimethylpyrrolidin-2-one (226 mg) and by the reaction and treatment in the same manner as in Preparation Example 48, the title compound (538 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]([C:13]2[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[OH:12])=[C:5]([CH:23]([CH3:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:4]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]([C:13]2[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=[C:5]([CH:23]([CH3:31])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:4]=1
Reactant: COc1ncc(C(O)c2cc(OC)c(OC)cc2C(C)Cc2ccccc2)c(OC)n1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: COc1ncc(C(=O)c2cc(OC)c(OC)cc2C(C)Cc2ccccc2)c(OC)n1
Yield: 67.9 %

Procedure:
To a solution of [4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-(2,4-dimethoxy-pyrimidin-5-yl)-methanol (0.418 g, 0.9 mmol) in 20 mL toluene was added MnO2 (0.335 g, 4.7 mmol). The mixture was warmed to reflux and H2O was removed via a Dean-Stark trap. After 1 hour the mixture was cooled, filtered through a pad of celite and concentrated in vacuo to give a crude oil. Purification via flash chromatography (7:3 hexane/ethyl acetate) afforded [4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-(2,4-dimethoxy-pyrimidin-5-yl)-methanone (0.258 g, 62%) as a clear oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O.N>CN(C)C=O.[Cu](I)I>[O:27]([C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Oc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 150 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
100 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one and 58 mg of phenol were dissolved in 10 ml of dimethylformamide, to which 84 mg of potassium carbonate and 6 mg of copper iodide were added, and the mixture was stirred at 150° C. for 5 hours. The reaction solution was cooled to room temperature, to which ammonia water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water and dried by magnesium sulfate anhydride, and the solvent was distilled off under a vacuum. The residue was refined by silica gel chromatography (hexane/ethyl acetate-based solvent), to obtain 66 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.C[CH2:21][N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:22][CH3:21])=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nccc(-c2cc(F)c(Cl)cc2F)c1C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
To the stirred solution of 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinic acid (1.7 g, 4.02 mmol) in DMF (0.5 mL) was added DIEA (2.81 mL, 16.06 mmol), HOBT (1.230 g, 8.03 mmol), EDC (1.155 g, 6.02 mmol) at 0° C. followed by addition of methylamine hydrochloride (0.488 g, 7.23 mmol). After stirring for 10 min, the ice bath was removed and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and washed with water (10 mL) followed by brine (10 mL). The organic layer was separated and dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)-N,2-dimethylnicotinamide (1 g, 2.123 mmol, 53% crude yield) as a brown solid which was taken to the next step without purification. LC/MS (ESI) m/e 297.3 [(M+H)+, calcd for C14H12ClF2N2O 297.1]; LC/MS retention time (method B): tR=0.76 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[O:24]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1>>[O:24]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH:27]([NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCS(=O)(=O)C1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCS(=O)(=O)C2)cn1
Yield: 54 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1,1-dioxo-tetrahydro-thiophen-3-ylamine instead of methylamine, to the title compound (150 mg, 54%) which was obtained as a white solid. MS: m/e=428.2 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][OH:30])[C:21]=1[CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]=1[CH3:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C/C(=C/CO)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-1-methyl-1-propenyl)benzene (120 mg) and triethylamine (32.8 mg) in dichloromethane (1.2 ml) was dropwise added methanesulfonyl chloride (34 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) as colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16]1[NH:35][C:19]2=[CH:20][C:21]3[C:22]([CH3:34])([CH3:33])[C:23](=[O:32])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:25]=3[CH:26]=[C:18]2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]([C:16]1[NH:35][C:19]2=[CH:20][C:21]3[C:22]([CH3:34])([CH3:33])[C:23](=[O:32])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:25]=3[CH:26]=[C:18]2[N:17]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c([C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)nc3cc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c([C@@H](N)Cc4ccccc4)nc3cc21
Yield: 108 %

Procedure:
[(S)-1-(7,7-Dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (50 mg) is treated with a mixture of 1,4-dioxane (5 ml) and hydrochloric acid (2 N; 5 ml) for 15 min at 50° C. The solvents are evaporated and the residue lyophilized. The desired compound (43 mg) is obtained as a hydrochloride (white solid).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:27]1[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccncc2)c1
Yield: 41.2 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (130 mg, 0.291 mmol), pyridine-4-boronic acid (54 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (46 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J=1.6, 4.5 Hz, 2H), 7.61-7.39 (m, 4H), 7.15 (dd, J=8.6, 10.2 Hz, 1H), 5.31 (s, 1H), 4.69-4.57 (m, 1H), 3.40-2.07 (m, 6H), 1.69 (d, J=10.8 Hz, 6H), 2.06-0.74 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.6, 143.3, 141.6, 141.5, 126.7, 126.6, 124.9, 124.8, 120.1, 119.9, 116.1, 115.9, 115.4, 115.1, 109.2, 71.4, 55.9, 55.0, 47.6, 46.7, 29.9, 25.6, 24.8, 19.8 ppm. Purity: 97% UPLCMS (210 nm); retention time 0.82 min; (M+1) 384.6.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:16][CH3:17])[C:5]1[CH:12]=[C:11]([S:13][CH3:14])[C:8]([C:9]#[N:10])=[C:7]([OH:15])[N:6]=1.I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:17][O:16][CH:4]([O:3][CH3:2])[C:5]1[CH:12]=[C:11]([S:13][CH3:14])[C:8]([C:9]#[N:10])=[C:7]([O:15][CH:19]([CH3:21])[CH3:20])[N:6]=1
Reactant: CC(C)I
Reactant: COC(OC)c1cc(SC)c(C#N)c(O)n1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(SC)c(C#N)c(OC(C)C)n1
Temperature: 120 °C
Yield: 80 %

Procedure:
6-Dimethoxymethyl-2-hydroxy-4-methylsulfanyl-nicotinonitrile sodium salt synthesized as described by Mahata, P. K. et al. Tetrahedron 59, 2003, 2631-2639 (3.5 g, 13.3 mmol) in 40 mL of anhydrous DMF was heated at 120° C. while 2-iodopropane (1.6 mL, 16.0 mmol) was added dropwise. The resulting mixture was heated at 120° C. for another 30 min before it was cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, evaporated in vacuo. Purification on an Analogix MPLC system (SiO2 column) eluting with 10% EtOAc in hexanes yielded the titled compound as a light yellow solid upon standing (3.0 g, 80% yield).