Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH:10]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H-chromene (4.4g., 0.012 moles) was dissolved in a solution of dimethylamine in ethanol (28 ml., ~40% solution) and left to stand at room temperature for 48 hours. Removal of solvent gave the title product as an orange oil which was converted to the hydrochloride salt. Recrystallization from acetone gave a white solid (3.13g., 64%) m.p. 185°-187° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N:20]=O)=[C:12]([OH:22])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[C:27]1=[CH2:28]>CO>[CH3:36][N:29]1[C:27]2([O:22][C:12]3[CH:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:5][CH:6]=4)[C:19]4[C:14]([C:13]=3[N:20]=[CH:28]2)=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:26]([CH3:25])([CH3:37])[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: CCN(CC)c1ccc(-c2cc(O)c(N=O)c3ccccc23)cc1
Solvent: CO
Product: CCN(CC)c1ccc(-c2cc3c(c4ccccc24)N=CC2(O3)N(C)c3ccccc3C2(C)C)cc1
Yield: 36.6 %

Procedure:
A solution of 4-(p-diethylaminophenyl)-1-nitroso-2 -hydroxynaphthalene (0.85 g; 0.0027 mol) and 1,3-dihydro-1,3,3-trimethyl-2-methyleneindoline (0.5 g; 0.0029 mol) in methanol (60 ml) under nitrogen, was heated under reflux for 24 hours. The solution was then evaporated and chromatographed over silica (1 part diethyl ether to 10 parts pet. ether) to afford 1,3-dihydro-1,3,3-trimethyl-6'-(p-diethylaminophenyl)spiro[2H-indole-2,3'-[3H]naphth[2,1-b][1,4]oxazine] (0.47 g; 36%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH:19]([CH3:21])[CH3:20])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(Cl)(Cl)Cl>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:19]([C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][C:6]([O:22][CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1)([CH3:20])[CH3:21]
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4cc(OCCN5CCOCC5)ccc4c3n21
Temperature: 65 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and tetrabutylammonium bromide (0.30 g, 1.0 mmol) and a solution of 4-(2-chloroethyl)morpholine hydrochloride (0.21 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 110 mg of the title compound as white, mp 194-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=S.Cl.[NH:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH2:25].ClCCl>C(O)C>[CH2:30]([O:29][C:27]([CH2:26][NH:24][N:25]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:28])[CH3:31]
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(=S)c1ccccc1Cl
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CNN=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of 5-chloro-2-neopentylaminophenyl 2-chlorophenyl thioketone (0.54 g) in ethanol (7 ml) was added ethyl hydrazinoacetate hydrochloride (0.11 g). The mixture was stirred for one day at 70° C. To the reaction mixture was added dichloromethane (50 ml), which was washed with water and, then, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=15:1 v/v as an eluent) to give 0.16 g of an oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:35]O)[NH2:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[N:35]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:34]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1Cl
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 49 mg (51% of theory)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[N:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:6]=[C:5]([CH3:18])[N:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Yield: 44.3 %

Procedure:
tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.6 g, 6.5 mmol) and 4-chlorothiosalicylic acid (2.4 g, 13.1 mmol) were dissolved in pyridine (20 ml). The mixture was refluxed for 24 hrs. The solvent was evaporated, and residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.2 g, 46%) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]([F:28])([F:27])[F:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:22])([CH3:21])[CH2:13][C:14](=[O:20])[N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[CH3:23])[CH:7]=1.[CH2:29]([OH:32])[C:30]#[CH:31]>>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([CH3:23])=[C:8]([C:6]3[CH:7]=[C:2]([C:31]#[C:30][CH2:29][OH:32])[CH:3]=[CH:4][C:5]=3[O:24][C:25]([F:27])([F:28])[F:26])[CH:17]=2)[C:12]([CH3:21])([CH3:22])[CH2:13][C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(Br)ccc3OC(F)(F)F)cc21
Reactant: C#CCO
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C#CCO)ccc3OC(F)(F)F)cc21

Procedure:
Compound 57A was prepared from Compound 9B using a procedure similar to that described for Example 56A except that propargyl alcohol was used as the coupling partner. MS (electrospray): mass calculated for C24H24F3NO3, 431.45; m/z found 432.2, [M+H]+.
Reaction SMILES: [NH:1]([C:8](=O)[CH2:9][C:10]1[N:11]=[C:12]([S:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[S:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O1CCCC1>[NH:1]([CH2:8][CH2:9][C:10]1[N:11]=[C:12]([S:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[S:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Sc1nc(CC(=O)Nc2ccccc2)cs1)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1nc(CCNc2ccccc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a suspension of 2-{[4-(2-anilino-2-oxoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (2.9 g) obtained in Example 488-1 in tetrahydrofuran (30 mL) was added 1 mol/L borane-tetrahydrofuran complex (24 ml), and the mixture was stirred at room temperature overnight. Methanol was gradually added to the reaction mixture, and the mixture was stirred at room temperature overnight. The resin was collected by filtration, washed three times with methanol, and vacuum dried to give the title pale-brown resin (2.4 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([O:14][CH2:15][CH2:16]Br)([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>CN(C=O)C.C1OCCOCCOCCOCCOC1.[I-].[Na+]>[C:10]([O:14][CH2:15][CH2:16][O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OCCBr
Reactant: OC1CCOCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCOC1CCOCC1
Temperature: 50 °C
Yield: 64 %

Procedure:
Tetrahydropyran-4-ol (19.72 g; 0.193 mol) was added dropwise (rapid addition) to a suspension of sodium hydride (8.5 g; 0.213 mol) in DMF (200 ml) under argon. The mixture was heated at 50° C. for 40 minutes then cooled to ambient temperature. 2-tert-Butoxyethyl bromide (35 g, 0.193 mol), (J. Med. Chem. 1966, 361), was added dropwise followed by sodium iodide (approximately 1 g) and 15-crown-5 (20 drops). The mixture was heated at 105° C. for 1 hour. Upon cooling to ambient temperature the mixture was poured into a saturated solution of ammonium chloride and extracted with ether (2×1 l). The organic phase was washed with water, brine, dried (MgSO4) and the solvent evaporated off to give 4-(2-tert-butoxyethoxy)tetrahydropyran (25 g, 64%) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[O:8].B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:3]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(C(=CNC(=O)c2sc3ccc(C(F)(F)F)cc3c2O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NC=C(c1ccc(O)cc1)c1ccc(O)cc1)c1sc2ccc(C(F)(F)F)cc2c1O
Temperature: -50 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 3-hydroxy-N-[2,2-di-(4-methoxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]thiophe ne-2-carboxamide (200 mg) in dichloromethane (30 ml) cooled to -50° C. was added dropwise with stirring N boron tribromide in dichloromethane (2.9 ml). The reaction mixture was stirred at -50° C. for one hour, then the temperature allowed to rise to 0° C., and the reaction quenched by pouring into ice-saturated sodium hydrogencarbonate solution. The yellow solid that separated out was filtered, washed thoroughly with hexane and dried in vacuo to yield 104 mg (55%) of 3-hydroxy-N-[2,2-di-(4-hydroxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]thiophene-2-carboxamide; m/z 471 (M+).
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10]C)=[C:5]([CH3:12])[C:4]=1[CH2:13][CH2:14][NH2:15].[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[CH3:12][C:5]1[C:6]([OH:10])=[CH:7][C:8]([CH3:9])=[C:3]2[C:4]=1[CH2:13][CH2:14][NH:15]2
Reactant: COc1cc(C)c(OC)c(CCN)c1C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(O)c(C)c2c1NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2,5-dimethoxy-3,6-dimethylbenzene ethanamine (22.0 g, 105 mmol) in acetonitrile (100 ml) was added dropwise a solution of cerium diammonium nitrate (120.9 g, 220 mmol) in acetonitrile (100 ml) and water (200 ml) with cooling on ice over 20 minutes. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of a solution of sodium hydrogen carbonate (138 g, 1640 mmol) in water (400 ml) and ethyl acetate (400 ml) and stirred at the same temperature for 30 minutes. After removing of insolubles by filtration, the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The combined organic layers were washed with saturated brine, and then treated with a solution of 80% sodium hydrosulfite (48 g, 220 mmol) in water (400 ml). The mixture was made basic using a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, purified by silica gel chromatography with a small amount of silica gel and eluted with ethyl acetate. The solvent was removed under reduced pressure, and the resultant oil was crystallized front diethyl ether to obtain 14.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[N:27]#[C:28]Br>CCO.C(Cl)Cl>[NH2:27][C:28]1[N:14]([C@@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[C:3]2[CH:4]=[C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ccc2N)CC1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(N4CCOCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
The cis-4-(2-amino-5-morpholinophenylamino)-N-isopropylcyclohexanecarboxamide (315 mg, 0.874 mmol) was dissolved in EtOH (5 mL), and cyanogen bromide (139 mg, 1.311 mmol) was added. The reaction was stirred at RT. After 16 hours, the reaction was diluted with DCM (50 mL) and washed with 1 N aqueous NaOH. The organic layer was concentrated to provide cis-4-(2-amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide as a light purple solid (210 mg, 62.3% yield). MS, m/z (C21H31N5O2): calcd, 385.2. found, 385.8 [M+H].
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)[CH:24]=1)=[O:21])=[CH:15][CH:14]=[CH:13]2.Cl[C:40]1[N:45]=[CH:44][N:43]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[CH:41]=1>C1(C)C=CC=CC=1>[CH3:38][C:36]1[N:35]=[CH:34][N:33]([C:25]2[CH:24]=[C:23]([NH:22][C:20]([C:16]3[C:17]4[C:12](=[CH:11][C:10]([O:9][C:40]5[CH:41]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[N:43]=[CH:44][N:45]=5)=[CH:19][CH:18]=4)[CH:13]=[CH:14][CH:15]=3)=[O:21])[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=2)[CH:37]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O)ccc34)cc(C(F)(F)F)c2)cn1
Reactant: CC(=O)Nc1cc(Cl)ncn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(C(=O)Nc4cc(-n5cnc(C)c5)cc(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 110 °C
Reaction time: 50 h

Procedure:
Anhydrous tripotassium phosphate (848 mg, 4.0 mmol) is added to a stirred solution of 6-hydroxy-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1-naphthalenecarboxamide (411 mg, 1.0 mmol) in toluene (40 mL) under an argon atmosphere at 110° C. N-(6-Chloro-4-pyrimidinyl)-acetamide (252 mg, 1.5 mmol) is added and the mixture is stirred at 110° C. for a further 50 hours. The solvent is evaporated off under reduced pressure and the residue is washed with a saturated aqueous solution of NH4Cl and dried. The crude product is purified by recrystallisation from methanol to afford the title compound as a beige solid, m.p.: 291-293° C.
Reaction SMILES: I[C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[CH:39])[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:21]([NH:27][C:28]1[N:29]=[C:30]([OH:40])[C:31]2[CH:37]=[C:36]([C:38]#[C:39][C:2]3[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[CH:35]=[N:34][C:32]=2[N:33]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cn1[Si](C(C)C)(C(C)C)C(C)C
Yield: 56.7 %

Procedure:
A mixture of 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole (1.222 g, 3.0 mmol), 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (0.851 g, 3.15 mmol), Pd(PPh)2C12 (105 mg, 0.15 mmol), cuprous iodide (2 g mg, 0.15 mmol), and triethylamine (0.5 mL) in acetonitrile (50 mL) was heated at reflux for 4 hours. The resulting solution was cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with hexanes:ethyl acetate(2:1). The first major fraction is unchanged starting material (270 mg, 32%); the subsequent major fluorescent fractions were combined and concentrated in vacuo to give methyl 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]1-triisopropylsilylpyrrole-2-carboxylate as a pale yellow solid (935 mg, 57%, mp 163-165° C.): 1H NMR (CDCl3) δ 8.90 (br s, 1H), 8.52 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=1.4 Hz), 7.23 (d, 1H, J=1.4 Hz), 3.79 (s, 3H), 1.75 (sept, 3H, J=7.6 Hz), 1.31 (s, 9H), 1.10(d, 18H, J=7.6 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]3[C:13]=1[C:12]([C:14]([O:16]C)=[O:15])=[CH:11][C:10]3=[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)[C:19]=2[CH2:20][CH3:21])(=[O:3])[CH3:2].[OH-].[K+]>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]3[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10]3=[C:18]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=1)[C:19]=2[CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3c(NC(C)=O)ccc1n23
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)O)c3c(NC(C)=O)ccc1n23
Yield: 93.5 %

Procedure:
A mixture of methyl 7-acetylamino-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylate (17.15 g, 0.0368 mol) and 85% potassium hydroxide (36.4 g, 0.551 mol) in 1700 ml of methanol was refluxed for 16 hours. The mixture was filtered and the precipitate (shown to be starting material) was further refluxed for 48 hours in 800 ml of methanol and 17.4 g of 85% potassium hydroxide. The mixture was filtered and the filtrate was combined with the first filtrate. The resulting mixture was evaporated to nearly dryness and 1000 ml of water was added. The pH was adjusted to 1.0 with a 6M hydrochloric acid solution. The precipitate was filtered off and dried to afford 15.57 g (94%) of the title compound. M.p. 244-46° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.38 (t, 3H), 2.27 (s, 3H), 3.13 (q, 2H), 3.97 (s, 3H), 5.19 (s, 2H), 7.22 (q, 2H), 7.38-7.55 (m, 5H), 7.75 (d, 2H), 7.91 (s, 1H), 8.12 (d, 1H), 8.95 (d, 1H), 11.78 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[NH2:11][C@H:12]1[CH2:17][C@H:16]([CH3:18])[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][C@@H:16]([CH3:18])[CH2:17][C@H:12]([NH:11][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=2)[CH2:13]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1ncc(Br)c(Cl)n1
Reactant: C[C@H]1C[C@H](N)CN(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc(Br)c(N[C@H]2C[C@H](C)CN(C(=O)OCc3ccccc3)C2)n1

Procedure:
A solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (1.0 g, 4.2 mmol), (3S,5S)-benzyl 3-amino-5-methylpiperidine-1-carboxylate (2.7 g, 8.35 mmol) and triethylamine 1.3 g, 12.5 mmol) in dioxane (50 ml) were stirred for 16 hours. The reaction was concentrated and the residue dissolved in methylene chloride (50 ml) and washed with water. The organic layer was dried and concentrated and purified on a silica gel column with 10-20% ethyl acetate/dichloromethane as solvent to give (3S,5S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-5-methyl-piperidine-1-carboxylic acid benzyl ester as a viscous oil. MS (ES+): 452.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.[CH2:21]([C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([CH3:32])[C:24]=1[CH2:25]Cl)[CH3:22].C(N(C(C)C)CC)(C)C.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO.C(O)C.O.C(Cl)Cl.CN(C)C=O>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:25][C:24]3[C:27]([CH3:32])=[CH:28][C:29]([F:31])=[CH:30][C:23]=3[CH2:21][CH3:22])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: CCc1cc(F)cc(C)c1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCc1cc(F)cc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.4 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (0.7 g, 1.9 mmol), 2-ethyl-4-fluoro-6-methylbenzylchloride (0.26 g, 1.9 mmol) and diisopropylethylamin (0.54 g, 4.2 mmol) were added to dimethylformamide (5 ml) and stirred at room temperature for 1 h. Methylene chloride and water were added to the reaction mixture, the organic layer was separated, dried and evaporated under reduced pressure. The residue was solved in ethylacetate and ethanol and metanesulfonic acid (0.2 g, 2 mmol) was added. The product was filtred off and was solved in methylene chloride:methanol (2:1) and an excess of potassium carbonate. The solids were filtred off and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. The residue was solved in ethylacetate and methansulfonic acid (0.04 g, 0.4 mmol) was added. The salt was filtred off to give 0.2 g (23%) of the title compound.