Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[CH3:23][C:24]1[C:28]([C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[C:27]([CH3:38])[NH:26][C:25]=1[CH:39]=O.N1CCCCC1>C(O)C>[CH3:23][C:24]1[C:28]([C:29]([N:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)=[O:30])=[C:27]([CH3:38])[NH:26][C:25]=1/[CH:39]=[C:10]1\[C:2](=[O:1])[NH:3][C:4]2[C:9]\1=[CH:8][C:7]([S:11]([CH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18])(=[O:12])=[O:13])=[CH:6][CH:5]=2
Reactant: N#Cc1ccccc1CS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4C#N)cc32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.7 %

Procedure:
To a solution of 2-(2-oxo-2,3-dihydro-1H-indole-5-sulfonylmethyl)-benzonitrile (100 mg, 0.32 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (79 mg, 0.32 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 10:90 to provide 123 mg (71%) of 2-{3-[1-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonylmethyl}-benzonitrile as a pale orange solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)(=O)=O.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[N:8][CH:9]=1
Reactant: O=S(=O)(Oc1ccc(Cl)cn1)C(F)(F)F
Reactant: C[Sn](C)(C)Cl
Product: C[Sn](C)(C)c1ccc(Cl)cn1

Procedure:
5-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 5-chloro-2-(trimethylstannyl)pyridine. The crude material (˜4 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (0-50% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.48 (25% ethyl acetate/hexanes); MS (Q1) 427 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH2:22][CH2:23]O)(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCO)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Temperature: 2.5 °C
Yield: 43.5 %

Procedure:
To a 0-5° C. stirred suspension of 2-[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidine-6-sulfonyl]ethanol (41 mg, 0.1 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (0.5 mL) under N2 was added dropwise methanesulfonyl chloride (9.3 μL, 0.12 mmol). Additional charges of methanesulfonyl chloride (9.3 μL, 9.3 μL) were added after 45 minutes, and 1.5 hours, the latter with additional triethylamine (50 μL). After reaction for a total of 2.5 hours, the cold solution was quenched with 5% aqueous sodium bicarbonate, then extracted with ethyl acetate (2×). The combined organic extracts were dried (MgSO4) then filtered through a pad of flash SiO2. The filtrate was concentrated to a solid that was crystallized from ethyl acetate to leave the product (17 mg, 44%), mp 214-217° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=2)[CH2:4][N:3]1[CH2:16][N:17]1[CH:21]=[C:20](C#N)[N:19]=[CH:18]1.[NH3:24].[CH3:25]O>[Pd]>[NH2:24][CH2:25][C:21]1[N:17]([CH2:16][N:3]2[CH2:4][CH:5]([C:7]3[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[CH:8]=3)[CH2:6][C:2]2=[O:1])[CH:18]=[N:19][CH:20]=1
Reactant: CO
Reactant: N#Cc1cn(CN2CC(c3cc(F)c(F)c(F)c3)CC2=O)cn1
Reactant: N
Agent: [Pd]
Product: NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reaction time: 6 h

Procedure:
In a 250 ml parr apparatus, Pd/C (0.1 g, 10% w/w) is added onto a solution of the enantiomerically pure (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile 79 (0.2 g, 0.624 mmol) in NH3/MeOH (3 M, 30 ml) and the suspension is stirred under an hydrogen pressure (50 psi) for 6 h. The reaction mixture is concentrated in vacuo, dissolved in AcOEt, dried over MgSO4, filtered and concentrated in vacuo to afford 0.14 g of crude 1-(5-aminomethyl-imidazol-1-ylmethyl)-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one a34 which is used as such in the next step.
Reaction SMILES: BrC1C=C2C3=C4C(=CC(Br)=CC4=CC=C3C=1)C=C2.C[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30](C)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.Br[C:35]1[C:36]2[C:41]([C:42](Br)=[C:43]3[C:48]=1[CH:47]=[CH:46][CH:45]=[CH:44]3)=[CH:40][CH:39]=[CH:38][CH:37]=2.[C:50]1([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:27]1([N:26]([C:23]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=2)[C:35]2[C:36]3[C:41]([C:42]([N:56]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[C:43]4[C:48]=2[CH:47]=[CH:46][CH:45]=[CH:44]4)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: Brc1cc2ccc3cc(Br)cc4ccc(c1)c2c34
Product: c1ccc(N(c2ccccc2)c2c3ccccc3c(N(c3ccccc3)c3ccccc3)c3ccccc23)cc1

Procedure:
Preparation analogous to Example 20a. Instead of 76.0 g (211 mmol) of dibromopyrene (isomer mixture) and 94.7 g (480 mmol) of bis(4-methylphenyl)amine, 70.9 g (211 mmol) of 9,10-dibromoanthracene and 81.2 g (480 mmol) of diphenylamine are used. Yield: 86.2 g (168 mmol), 79.7% of theory; purity 99% according to 1H-NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2].[H-].[Na+].I[CH3:51]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:51])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(COC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Reaction time: 15 h
Yield: 79.2 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol) in DMF (5 mL) were added sodium hydride (29.9 mg, 0.75 mmol), and iodomethane (106.2 mg, 0.75 mmol) at room temperature. The resulting suspension was stirred for 15 h and then the excess sodium hydride was quenched by slow addition of water (5 mL). The mixture was diluted with 1.0N hydrochloric acid (25 mL) and the organic compound was extracted into ethyl acetate (2×25 mL). The combined extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum afforded the crude residue which was purified by using an ISCO 40 g column to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (200 mg, 78%) as a light brown oil: ES(+)-HRMS m/e calcd for C38H50O9S (M+Na)+ 705.3068. found 705.3069.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[C:18]([O:32][CH3:33])[CH:17]=2)=[O:14])=[C:11]([CH3:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37](N1CCOCC1)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:34][CH:35]=1)[C:13](=[O:14])[N:15]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[C:18]([O:32][CH3:33])[CH:17]=1)[CH:37]=[CH:36]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN1CCOCC1
Reactant: COc1cc(NC(=O)c2ccc(OCc3ccccc3)cc2C)ccc1N1CC[C@@H](N2CCCC2)C1
Product: COc1cc(-n2ccc3cc(OCc4ccccc4)ccc3c2=O)ccc1N1CC[C@@H](N2CCCC2)C1

Procedure:
According to Method Q, 4-benzyloxy-N—((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-methoxy-phenyl)-2-methyl-benzamide was reacted with N-formylmorpholine. In this way the product was obtained with molecular weight 495.63 (C31H33N3O3); MS (ESI): 496 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][F:22])[N:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.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>[F:22][CH2:21][C:17]1[N:16]=[C:15]([C:14]#[C:13][CH2:12][CH2:11][C:9]2[N:10]=[C:3]3[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: FCc1cccc(C#CCCc2cn3cccc(Br)c3n2)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: FCc1cccc(C#CCCc2cn3cccc(-c4ccccc4)c3n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
To a solution of 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (compound 171(C), 301 mg, 0.84 mmol) and phenylboronic acid (50 mg, 1.3 mmol) in degazed DME (4.2 mL) was added 1.32 mL of a solution of K3PO4 2M (degazed before use). After stirring at room temperature for 5 min under N2, Pd(PPh3)4 (190 mg, 0.17 mmol) was added in one portion. The resulting mixture was heated at 80° C. for 4 h. The Mixture was cooled down to room temperature and diluted in AcOEt. The organic layer was washed twice with saturated NaCl, dried over magnesium sulfate, filtered and concentrated. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 60/40 as eluent) to afford 137 mg of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine (Yield: 46%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[Si](C)(C)C1C=CC([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][CH2:24]3)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][CH2:24]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Product: COc1ccc(-c2cccc3c2C=CC3)cc1
Yield: 89 %

Procedure:
The synthesis was performed by the same procedure as in Metallocene Compound A (1-1) by using 4-methoxyphenylboronic acid in place of 4-trimethylsilylphenylboronic acid in the synthesis of 4-(4-trimethylsilyl-phenyl)-indene to obtain a yellow liquid of 4-(4-methoxy-phenyl)-indene in a yield of 89%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:13][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenol (47, 1.0 g, 4.35 mmol), methyl iodide (0.7 mL, 10.8 mmol) and K2CO3 (3 g, 21.75 mmol) in acetone (10 mL) was heated to reflux while stirring overnight. Solid residue was filtered off and the filtrate was concentrated on warm water bath at atmospheric pressure (Caution: product was volatile) to afford 1-methoxy-3,5-bis(trifluoromethyl)benzene (48, 0.6 g, 56%) as clear oil: 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.30 (s, 1H), 3.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.O.[C:12]([O:15]CC)(=[O:14])C>[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]([OH:6])[C:12]([OH:15])=[O:14]
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Product: O=C(O)C(O)c1cccc(Cl)c1

Procedure:
A mixture of 158 g of 3-chlorobenzaldehyde, 111.6 g of trimethylsilylnitrile and a catalytic amount of zinc iodide was heated at 90° C. for 2 hours, with stirring. The reaction mixture was ice-cooled, and 350 ml of concentrated aqueous hydrochloric acid were added to it. The resulting mixture was then heated under reflux for 1 hour, after which it was mixed with water and with ethyl acetate. The ethyl acetate layer was separated and mixed with a 30% w/v aqueous solution of sodium hydroxide. The aqueous layer was separated, washed three times with ethyl acetate and then acidified with concentrated aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give the title compound as crystals, melting at 110°-114° C.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[F:24][C:25]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[C:26]=1[CH2:27][N:28]1[C:33]([CH3:34])=[C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:31](=[O:41])[N:30]([CH2:42][C@H:43]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29]1=[O:58].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[C:53]([O:52][C:51](=[O:57])[NH:50][C@H:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][N:30]1[C:31](=[O:41])[C:32]([N:35]2[CH2:36][CH2:37][N:38]([CH2:5][CH2:4][CH2:3][C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])[CH2:39][CH2:40]2)=[C:33]([CH3:34])[N:28]([CH2:27][C:26]2[C:59]([C:63]([F:65])([F:66])[F:64])=[CH:60][CH:61]=[CH:62][C:25]=2[F:24])[C:29]1=[O:58])([CH3:54])([CH3:55])[CH3:56]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: Cc1c(N2CCNCC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(N2CCN(CCCC(F)(F)C(F)(F)F)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a solution of 100 μl (0.416 mmol) of 4,4,5,5,5-pentafluoropentan-1-ol in 2 mL of dichloromethane were added 69 μl (1.2 eq) of triethylamine and 36 μl (1.1 eq) of methanesulfonyl chloride in the order, followed by stirring at room temperature for 30 min. The solution was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate, filtrated and concentrated to produce a colorless oil. 60 μl of the oil, 30 mg of (R)-tert-butyl (2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-5-(piperazin-1-yl)-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.049 mmol), and 21 mg (0.149 mmol) of potassium carbonate were dissolved at 80° C. for 7 hrs in 2 mL of acetonitrile, with stirring. The solution was concentrated, diluted with dichloromethane, and washed with an aqueous saturated sodium bicarbonate solution. After concentration of the organic layer thus formed, the residue was purified by prep-TLC (eluent: hexane/ethyl acetate, 1/1) and dried in a vacuum to afford 8 mg of the compound as a colorless oil (yield 21%). 1H NMR (300 MHz, CDCl3) δ 1.36 (9H, s), 1.77 (2H, m), 2.14 (4H, m), 2.36 (3H, s), 2.42 (2H, m), 2.53 (2H, m), 2.75 (2H, m), 3.61 (2H, m), 4.05 (1H, m), 4.28 (1H, m), 5.01 (1H, m), 5.33 (1H, m), 5.51 (1H, m), 5.82 (1H, d), 7.19-7.44 (7H, m), 7.55 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:25][N:26]([CH3:28])[CH3:27])[C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CNC
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: C=O
Solvent: CCO
Product: CCOC(=O)c1cc2c(CN(C)C)c(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred solution of ethyl N-(3,4-dichlorobenzyl)-5-hydroxyindole-2-carboxylate (2.1 g) in ethanol (50 ml) was added successively aqueous dimetylamine (40%, 0.5 ml) and aqueous formaldehyde (0.5 ml). The solution was allowed to stand overnight and the resulting crystals filtered and dried in vacuo to give the product as pale yellow crystals (1.7 g, 70%); NMR δ(CD3SOCD3) 1.24 (t, 3H), 2.23 (s, 6H), 3.81 (s, 2H), 4.24 (q, 2H), 5.75 (s, 2H), 6.82 (d, 1H), 6.90 (dd, 1H), 7.30 (m, 3H), 7.50 (d, 1H); M/z (+) 423.421 (MH−), 378, 376.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Br:20][CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1
Reactant: BrBr
Reactant: OCCC1(O)CCc2ccccc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1(CCBr)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a 0° C. solution of triphenylphosphine (1.03 g, 3.93 mmol), in CH2Cl2 (15 ml) was added slowly a solution of bromine (0.192 ml, 3.74 mmol) in CH2Cl2. After 1 hour stirring at room temperature, the reaction mixture was cooled to 0° C. and treated slowly with a solution of (RS)-2-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.72 g, 3.74 mmol) in CH2Cl2 (15 ml). After 1.5 hour stirring at room temperature, the reaction mixture was again cooled to 0° C., treated slowly with triethylamine (0.52 ml, 3.74 mmol), washed successively with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-2-(2-bromo-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.58 g, 61%) as a colorless oil, MS: m/e=255.1 (M).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:76])[C@H:13]([NH:35][C:36](=[O:75])[C@H:37]([NH:45][C:46](=[O:74])[CH2:47][C@H:48](O)/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[Li+].[OH-:79].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:38]([C@H:37]1[NH:45][C:46](=[O:74])[CH2:47][C@@H:48](/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:79][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:7])[C:8]2([CH2:10][CH2:9]2)[NH:11][C:12](=[O:76])[C@@H:13]([CH2:14][S:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:35][C:36]1=[O:75])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: [OH-]
Reactant: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C1C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC(=O)C2(CC2)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)N1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 4 (305 mg, 0.29 mmol, 1 eq) in THF (10 mL) at 0° C. was added a solution of LiOH (10.3 mg, 0.43 mmol, 1.5 eq) in H2O (2 mL) dropwise. The mixture was stirred for 2 h, then quenched with 1N HCl (3 mL) and brine (10 mL). The organic layer was separated and the resulting aqueous layer was further extracted with EtOAc (2×15 mL) and (15 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting carboxylic acid was then dried on the high-vacuum pump for 2 h. To a solution of MNBA (118 mg, 0.34 mmol, 1.2 eq) and DMAP (84 mg, 0.69 mmol, 2.4 eq) in CH2CL2 (200 mL) was added a solution of the crude carboxylic acid in CH2Cl2 (130 mL) and THF (20 mL) dropwise over 3 h. The reaction mixture was then left to stir up at rt overnight. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (1:9→0:1) to yield 5 as a white solid (171 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=O)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[CH:19])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of compound 2a (562 mg, 1.80 mmol) in MeOH (10 mL), solid K2CO3 (0.749 g, 5.41 mmol) was added followed by dimethyl(1-diazo-2-oxopropyl)phosphonate (382 mg, 1.98 mmol) in MeOH (5 mL). The reaction was stirred at rt for 12 h and concentrated. The residue was dissolved in DCM (40 mL) and washed with water (25 mL). The aqueous layer was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with 1:1 EtOAc/heptane, filtered and dried to give compound 80a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C12H11BrN4O: 307.0 (M+H). found: 307.1.
Reaction SMILES: [CH2:1]1C(=O)N(Br)C(=O)C1.[F:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:26]([OH:28])=[O:27])[C:18](=[O:33])[CH:17]=2)=[C:12]([CH2:36][NH:37]C(OC)=O)[CH:11]=1>C(Cl)Cl>[C:36]([C:12]1[CH:11]=[C:10]([F:9])[CH:35]=[CH:34][C:13]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([O:28][CH3:1])=[O:27])[C:18](=[O:33])[CH:17]=1)#[N:37]
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3C#N)cc2=O)c1
Reaction time: 1.5 h

Procedure:
NBS (0.69 g, 3.85 mmol) was added to a solution of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5 h, solvent removed on rotary evaporator. Solid dissolved in EtOAc and hexane added, resulting in a solid precipitate. Solid filtered. Solid subsequently dissolved in DCM and washed with water. Organic layer dried over Na2SO4, filtered, and concentrated. Pale yellow solid dried in vacuo (1.47 g, 72%).