Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[CH3:15][N:14]1[C:8](=[O:9])[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH:12][C:11](=[O:13])[CH2:16]1
Reactant: CNCC(=O)O
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N(C)CC(=O)N2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 14.0 g (79 mmol) of 6-methylisatoic acid anhydride, 7.04 g (79 mmol) of sarcosine and 80 ml of dimethyl sulphoxide is stirred at 110° C. for 3 hours. The red coloured solution is evaporated in a high vacuum. The residue is treated with 80 ml of ethanol, the product crystallising out. There is obtained 3,4-dihydro-4,6-dimethyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 200°-202° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:26][CH2:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=1)=[O:22].C(Cl)Cl>C1COCC1>[CH3:19][O:20][C:21]([C:23]1[CH2:24][N:25]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:26][CH2:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:22]
Reactant: COC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(O)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TBAF (9.50 g, 30 mmol) was added to a sol. of compound B1 (13.4 g, 30 mmol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. CH2Cl2 was added, and the mixture was washed with aq. sat. NH4Cl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (10.0 g, quantitative yield) that was used further without purification. LC-MS: tR=0.92 min; ES+: 334.23.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>CO.C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1ccccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COCCNc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The residue 109A was dissolved in methanol (60 mL) and acetic acid (4 mL). Zinc metal (3.24 g, 49.6 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was decanted off from unreacted zinc metal. The solvent was removed under vacuum and resuspended in ethyl acetate (30 mL). The precipitate was removed by filtration on a Buchner funnel with Celite. Solvent was removed from the filtrate and the residue was purified by column chromatography (2% MeOH/DCM) to give the product N1-(2-methoxyethyl)benzene-1,2-diamine (109B) as a red oil (422 mg, 72% yield over two steps). ESI-MS:m/z 167.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C.O>[CH2:41]([S:42]([NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:11][N:10]=2)[CH2:7][CH2:8]1)(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1cnc(N2CCC(CNS(=O)(=O)Cc3ccccc3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To 0.028 g (0.066 mmol) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide in a mixture of acetonitrile (0.5 mL) and saturated aqueous sodium carbonate (0.5 mL) is added 0.015 mg (0.079 mmol) of phenylmethanesulfonyl chloride. The mixture is stirred overnight at room temperature then diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography to give 0.027 g (72%) of the title compound (109) as a clear resin. [M+H]+=577.7.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH:12]=[CH:13][CH:14]=1
Reactant: OCC(O)Cc1nccn1CCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Product: OCC(O)Cc1nccn1CCCc1cccc(O)c1
Yield: 99.9 %

Procedure:
Using 3-(1-[3-(3-benzyloxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (1.30 g) and 10% palladium carbon (0.195 g), the same reaction as Reference Example 11-(v) was carried out to yield the titled compound (0.979 g) as a colorless oily substance.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:22]([O-])([OH:24])=[O:23].C(O)(=O)C>S(=O)(=O)(O)O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=4)=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([N+:22]([O-:24])=[O:23])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(-c2ccncc2)nc2c1cnn2C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccncc2)nc2c1c([N+](=O)[O-])nn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclopentyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-amine (4.6 g, 0.016 mol) in sulfuric acid (60 ml) in an ice-bath was added dropwise 70% nitric acid (36.8 ml). The reaction mixture was warmed to room temperature, stirred for 30 minutes then heated on a steam bath for 3/4 hour. The reaction mixture was added to ice-water/50% sodium hydroxide and the pH was adjusted to 4-5 with acetic acid. The product was collected by filtration and washed with water. The solid residue was purified by preparative thin layer chromatography on silica eluting with ethyl acetate (100%) to afford, after recrystallization from ethyl acetate, 0.81 g (16%) of 1-cyclopentyl-3-nitro-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 239°-241° C. when dried for 16 hours at 110° C. in high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:4][CH:3]=1.BrC[CH:19]1[CH2:21][CH2:20]1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:10]2[CH2:11][CH:19]2[CH2:21][CH2:20]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(/C=C/CC2CCCCN2)cc1
Reactant: BrCC1CC1
Solvent: CC#N
Product: Fc1ccc(/C=C/CC2CCCN2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
In a reactor protected from moisture, there are introduced 2.3 g (0.010 mol) of (E)-2-(p-fluorocinnamyl)piperidine (Preparation 2B) dissolved in 25.2 ml acetonitrile, followed, during 2 min, by 1.56 g (1.1-0.012 mol) bromomethylcyclopropane. The medium is kept stirring at ambient temperature for 1 h 30 min, is raised to 60° C. for 4 h, and is then lowered to 20± 3° C. for 16 h. The solvent is evaporated under vacuum and on a water bath. The oily residue is dissolved in water, acidified and extracted with ether. After decanting, the cooled aqueous phase is alkalinized with soda, extracted with ether and washed with saturated NaCl solution. The organic phase is dehydrated over Na2SO4 and the solvent is then removed by distillation. The residue is purified by the Chromatoflash technique, elution being carried out with a 90:10 v/v mixture of methylene chloride and 10% ammoniacal MeOH, and is then subjected to a second acid-alkali treatment. (E)-2-(p-fluorocinnamyl)-1-(cyclopropylmethyl)pyrrolidine is obtained in the form of a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14](Cl)=[N:13][CH:12]=1)([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([N:1]=[N+:2]=[N-:3])=[N:13][CH:12]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cnc(N=[N+]=[N-])cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Sodium azide (1.51 g, 23.2 mmol) was added to a suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid tert-butyl ester (40) (3.23 g, 7.73 mmol) in DMF (60 mL). The reaction mixture was heated to 80° C. and stirred for 16 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with water, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (CH2Cl2) (repeated) provided the desired product (41) (1.41 g, 43%).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.CS(Cl)(=O)=O.O.[OH:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:25]2[C:24](=[O:36])[C:18]3[C:17](=[CH:22][C:21]([OH:23])=[CH:20][CH:19]=3)[O:16][CH:5]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: CCOCC
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1OC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
In a similar manner to Example 2.1 above, 1-(2,4-dihydroxyphenyl)-2-(3,4-dimethoxy-phenyl)-ethanone dissolved in DMF had added boron trifluoride diethyl etherate followed by methanesulfonyl chloride in DMF. Addition of water to the reaction mixture afforded 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([C:19]1([CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21][CH2:20]1)[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:23][C:19]2([CH2:17][CH3:18])[CH2:22][O:21][CH2:20]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(COc2ccc(Br)cc2C=O)COC1
Temperature: 140 °C
Yield: 47.8 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added toluene-4-sulfonic acid 3-ethyl-oxetan-3-ylmethyl ester (19 g, 70 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (10 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=3)=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:17][CH:16]=3)=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:30])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)cnc3o2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)cnc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
t-Butyl 4-(5-cyanofuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solvent of pyridine (16 ml) and triethylamine (4 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 18 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give t-butyl 4-(5-thiocarbamoylfuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate as a yellow solid. This solid was dissolved in acetone (15 ml) and methyl iodide (1.0 ml) was added, which was followed by refluxing under heating for 1.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[5-[(1-methylthio)iminomethyl]furo[2,3-b]pyridine-2-carbonylamino]phenoxyacetate as a yellow solid. Methanol (15 ml) and ammonium acetate (150 mg, 1.95 mmol) were added and the mixture was refluxed under heating for 2 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform/methanol=5/1) to give 35 mg of compound (238) as a yellow solid (11% in 3 steps).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([Br:41])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Br:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)CBr)cc1Br
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(Br)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(3-bromo-4-methoxyphenyl)ethanone (4.4 g) and N,N-dimethylformamide (300 mL) was added 60% sodium hydride (0.57 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (3.4 g, 43%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:22])=[C:7]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[CH:8]=1)#[CH:2].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:16])([F:17])[F:18])[CH2:14][C@:9]([C:7]2[CH:8]=[C:3]([C:1]#[C:2][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=3)[CH:4]=[CH:5][C:6]=2[F:22])([CH2:20][F:21])[N:10]=1
Reactant: C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Reactant: N#Cc1ccc(Br)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#Cc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (70 mg, 0.220 mmol), 6-bromonicotinonitrile (60.4 mg, 0.330 mmol), triethylamine (92 μl, 0.660 mmol), tetrakis (25.4 mg, 0.022 mmol), and copper(I) iodide (8.38 mg, 0.044 mmol) in 2 mL of THF in a microwave vial was heated at 80° C. for 20 min. The reaction mixture was filtered and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min. The desired fractions were combined, neutralized with 1N NaOH, extracted with 3×25 mL of DCM, dried over Na2SO4 and concentrated to afford the title compound as a white solid: 49 mg, 53% yield. MS m/z=421.0 [M+H]+. Calculated for C20H13F5N4O: 420.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.N#N.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1O
Reaction time: 3 h

Procedure:
To compound (3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (35.0 g, 75.8 mmol) was added methanol (150 mL). This solution was transferred to a Parr bottle and Pd/C (10% wt/wt on activated carbon) was added portion-wise while maintaining a N2 atmosphere through the reaction mixture. Hydrogen pressure (60 psi) was then applied and the vessel shaken for 3 hours, after which HPLC showed complete consumption of the starting material. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give (3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup. The crude product was dissolved in 1 M aqueous HCl solution (450 mL) and washed with chloroform (8×250 mL). The aqueous layer was then saturated with solid NaCl (100 g) and the solution was extracted with dichloromethane (8×200 mL). The combined dichloromethane extracts were dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to give 3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup; 1H NMR (400 MHz, D2O) δ 7.01 (d, H, J=8.0), 6.86-6.83 (m, 2H), 4.42-4.36 (m, 1H), 4.02 (overlapping dt, 1H, J=5.2, J=10.1), 3.85 (s, 3H), 3.67-3.55 (m, 1H), 3.46-2.81 (m, 7H), 2.77-2.70 (m, 1H), 2.34-2.27 (m, 1H), 2.11-1.74 (m, 5H), 1.41-1.10 (m, 4H); IR: 3439 (O—H stretch), 1592, 1510, 1098, 1022 cm−1; MS (ESI) 336.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>CO>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4]/[C:11](=[CH:10]/[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cc(F)ccc1F
Solvent: CO
Product: COC(=O)/C=C(/Nc1cc(F)ccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 2,5-difluoroaniline (X1) (3.00 mL, 29.9 mmol) in MeOH (30 mL) was added dimethyl acetylenedicarboxylate (P2) (DMAD, 4.44 mL, 35.9 mmol). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (gradient 0-30% EtOAc in Hex) to give dimethyl (2E)-2-[(2,5-difluorophenyl)amino]but-2-enedioate (X2). ES-MS [M+1]+=272.2.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[O:1][N:2]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cccc(C#N)c1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.59 (s, 1H), 7.75 (t, J=8.1 Hz, 1H), 7.88 (dt, J=8.0, 1.4, 1.2 Hz, 1H), 8.21-8.30 (m, 1H), 8.31-8.37 (m, 1H), 8.71 (d, J=2.7 Hz, 1H), 8.77 (dd, J=2.5, 1.5 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].P(Br)(Br)[Br:20]>N1C=CC=CC=1.C(OCC)C>[Br:20][CH2:1][C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCC#CCC#CCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCC#CCC#CCC#CCBr

Procedure:
A mixture of 5 g of 2,5,8-heptadecatriyn-1-ol, one drop of pyridine and 2 g of phosphorus tribromide in 20 cm3 of ethyl ether is heated under reflux for 3 hours. The ether phase is then washed initially with sodium bicarbonate and then with water, and then dried over magnesium sulphate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[CH3:11]
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: BrCCCCBr
Product: Cc1[nH]c2ccc(OCCCCBr)cc2c1C

Procedure:
In analogy to example 3.1, 2,3-Dimethyl-1H-indol-5-ol [for preparation see for example: Roth, H. J.; Lepke, P. Synthesis of indole and carbazole derivatives by condensation of α-hydroxyketones and aromatic amines. Arch. Pharm. (Weinheim) (1972), 305(3), 159-71.] and 1,4-dibromobutane were converted to yield 5-(4-Bromo-butoxy)-2,3-dimethyl-1H-indole as white solid, mp 119-120° C., MS: 295 (M, 1Br).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 280 mg, 90%).