Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Si]([O:13][CH2:14][C:15]#[C:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])(C(C)(C)C)(C)C>CO>[F:19][C:18]([F:21])([F:20])[C:17]1[CH:16]=[C:15]([CH2:14][OH:13])[O:3][N:2]=1
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cc(C(F)(F)F)no1
Yield: 31.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.694 g 0.010 mol, 1 equ) and 0.02 g sodium hydroxide in 25 mL methanol was added 5-(tert-butyldimethylsilyloxy)-1,1,1-trifluoropent-3-yn-2-one (2.66 g 0.010 mol, 1 equ) and the mixture was heated to reflux for 3 h. The reaction mixture was extracted with ethyl acetate and purified by chromatography on silica gel (50 g) using a gradient of heptane:ethyl acetate=9:1 to 1:1. to yield 0.524 g of the title compound as colorless oil, MS 167 (M.)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 399 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:1][C:2]2[C:11]3[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[C:6]=3[CH:5]=[N:4][C:3]=2[CH3:22])=[CH:26][CH:27]=1)#[N:32]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Product: Cc1ncc2c(c1OCc1ccc(C#N)cc1)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 75.2 %

Procedure:
The coupling of 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (874 mg, 3.24 mmol) and α-bromo-p-tolunitrile (1.2 g, 6.17 mmol), as described in Example 1, gave 4-[5-(4-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1ylmethyl]-benzonitrile (83) (1.0 g, 84% yield) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].CO[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][CH2:29][N:28]=1>COCCO>[N:13]1[N:12]=[C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[F:23])[N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:27]=12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: COC1=NCCCc2ccccc21
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCCc1ccccc1-2

Procedure:
A mixture of 90 mg (0.26 mmol) of tert-butyl [(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 45.5 mg (0.26 mmol) of 1-methoxy-4,5-dihydro-3H-2-benzazepine (Intermediate 10), and 3.5 mL of 2-methoxyethanol was stirred at reflux for 43 h. The cooled solution was concentrated, and the residue was purified by preparative HPLC (C18 reverse phase column, 20-90% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a colorless oil. LC-MS 473 (M+1).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:2]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([N:2]3[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]4[CH2:5][CH2:6][CH:1]3[CH2:8][CH2:7]4)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1NC2CCC1CC2
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Product: CCOC(=O)C1C2CCC(CC2)N1S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1

Procedure:
Ethyl 2-azabicyclo[2.2.2]octane-3-carboxylate is subjected to a reaction similar to the reaction (c) of Example 1 using [4-(4-methoxyphenyl)phenyl]sulfonyl chloride in place of 4-methoxybenzenesulfonyl chloride, to give ethyl 2-{[4′-methoxy(1,1′-biphenyl)-4-yl]sulfonyl}-2-azabicyclo[2.2.2]octane-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:13]([CH3:15])=[CH2:14]>C1COCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:15])=[CH2:14])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: C=C(C)Br
Reactant: OB(O)c1cc(Br)cc(Br)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+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(Br)cc(Br)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a degassed mixture of 5.0 g (17.9 mmol) of 3,5-dibromophenylboronic acid in 50 mL of THF and 25 mL of 2 M Na2CO3 (aqueous) was added 1.13 g (0.975 mmol) of Pd(PPh3)4 and 2.3 mL of 2-bromopropene. The mixture was stirred at 40° C. for 5 h, and the mixture was extracted with EtOAc. The organic layer was washed with 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 1,3-dibromo-5-(prop-1-en-2-yl)benzene with some impurity.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][C:4]=1[NH:17][C:18](=O)[C@H:19]([CH3:25])[CH2:20][O:21][CH2:22][O:23][CH3:24])=O.CO.[NH3:29]>>[CH2:10]([O:9][C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[N:17]=[C:18]([C@H:19]([CH3:25])[CH2:20][O:21][CH2:22][O:23][CH3:24])[N:29]=[CH:1]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N
Reactant: CCCCCCCOc1ccc(NC(=O)[C@H](C)COCOC)c(C=O)c1
Solvent: CO
Product: CCCCCCCOc1ccc2nc([C@H](C)COCOC)ncc2c1
Temperature: -78 °C
Yield: 75.1 %

Procedure:
(R)—N-(2-Formyl-4-heptyloxyphenyl)-3-methoxymethoxy-2-methylpropanamide (2.50 g, 0.00684 mol) was dissolved in methanol (200 mL, 5 mol), and cooled to −78° C., followed by ammonia (20 g, 1 mol) bubbling for 3 hours. The reaction mixture was then transferred to a pre-cooled high pressure reactor, and heated at 130° C. for 15 hours (310 psi). Solvent was removed, and the crude mixture was purified via chromatography (SiO2, 40 g, 0-60% ethyl acetate/hexanes) to give the desired product (1.78 g, 75%). 1H NMR (CHLOROFORM-d) δ: 9.26 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.52 (dd, J=9.2, 2.6 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 4.55-4.68 (m, 2H), 4.02-4.16 (m, 3H), 3.85 (dd, J=9.4, 6.4 Hz, 1H), 3.45-3.61 (m, 1H), 3.27 (s, 3H), 1.79-1.95 (m, 2H), 1.45-1.57 (m, 2H), 1.27-1.45 (m, 9H), 0.91 (t, J=6.7 Hz, 3H). MS (M+1): 347.30.
Reaction SMILES: [CH2:1]([Si:13](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27]>CCCCCCC>[CH2:1]([Si:13]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Si](Cl)(Cl)Cl
Reactant: COCCOCCOCCO
Solvent: CCCCCCC
Product: CCCCCCCCCCCC[Si](OCCOCCOCCOC)(OCCOCCOCCOC)OCCOCCOCCOC

Procedure:
The procedure of Example 1 was repeated with 151.8 g (0.50 mole) of dodecyltrichlorosilane and 200 g. of heptane. Under nitrogen 254.2 g (1.55 mole) of 2-(2-(2-methoxyethoxy)ethoxy)ethanol was added over 3 hours at 80° C. followed by heating of the reaction for an additional 48 hours. Vacuum stripping of all volatiles left 350 g of the clear, pale yellow liquid product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.CN(C)C(=N)N(C)C.Cl.[N+:35]([CH3:38])([O-:37])=[O:36]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH2:38][N+:35]([O-:37])=[O:36])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc2c(C)cn(CCCc3ccccc3)c2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 65 °C

Procedure:
A stirred solution of methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-propenoate (0.263 g, Reference Example 39) in nitromethane (5 ml) was treated with tetramethylguanidine (0.091 g). The mixture was heated to 65° C. for 2 hours then treated with a further aliquot of tetramethylguanidine (0.091 g). After heating at 65° C. for a further hour the reaction mixture was cooled to room temperature then poured into hydrochloric acid (20 ml, 1N) then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (1:2, v/v) as eluent to yield the title compound (0.296 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]=[CH:9][Cl:10])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([CH2:7][CH:8]=[CH:9][Cl:10])[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][Cl:19])[CH3:2]
Reactant: CCOC(=O)CNCC=CCl
Reactant: O=C(Cl)CCCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC=CCl)C(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Into a 100 ml four-necked flask there were placed 17.8 g of N-(3-chloroallyl)glycine ethyl ester, 15.2 g of triethylamine and 50 ml of benzene, and then 16.9 g of γ-chlorobutyryl chloride was gradually dropwise added thereto at room temperature with thorough stirring. Thereafter, the mixture was stirred for 1 hour at 60° C. After cooling, the reaction solution was washed with water, the benzene layer was dried over anhydrous sodium sulfate and the benzene was removed under reduced pressure. The residue obtained was distilled under reduced pressure to obtain 23.7 g of the objective N-(3-chloroallyl)-N-γ-chlorobutyryl glycine ethyl ester (b.p.2 167 - 170° C, nD23.0 1.4884).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1I.[NH2:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[N+:30]([O-:32])=[O:31].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[C:18]1[CH:19]=[CH:20][C:15]([NH2:14])=[C:16]([N+:30]([O-:32])=[O:31])[CH:17]=1
Reactant: Fc1cccc(OC(F)(F)F)c1I
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2c(F)cccc2OC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
2-Fluoro-1-iodo-6-trifluoromethoxybenzene (612 mg, 2.00 mmol, prepared as described in WO2005/097136), 4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 687 mg, 2.60 mmol), and (dppf)PdCl2.DCM (0.05 eq., 81.6 mg, 0.100 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (10 mL) and 2M aq Na2 CO3 (4 mL) were added via syringe. The vial was capped tightly and placed in a heating block where the reaction was stirred at 90° C. for 24 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed sequentially with water and brine. The organic extract was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:3, v/v over 30 min, yielding 548 mg (87%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.21 (s, 1H), 7.30-7.47 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 7.14 (t, J=8.6 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H), 5.37 (br. s., 2H).
Reaction SMILES: [C:1]([CH:3]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])#[CH:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[F:16][C:12]1[C:11]([F:17])=[C:10]2[C:15]([CH:2]=[CH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:9]2)=[CH:14][CH:13]=1
Reactant: C#CC(CCCCC)Oc1cccc(F)c1F
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: CCCCCC1C=Cc2ccc(F)c(F)c2O1

Procedure:
62.0 g (0.26 mol) of 1-(1-ethynylhexyloxy)-2,3-difluorobenzene are heated at 195° C. for 2 h in 390 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with 1 N HCl. The organic phase is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-pentane:1-chlorobutane=5:1), giving 7,8-difluoro-2-pentyl-2H-chromene as a brown oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:8][C:7]=1[NH2:21])C.Cl.II>C(O)C>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][C:4](=[O:3])[NH:21]2)=[CH:11][CH:10]=1)=[O:20]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2cccc(N)c2)cc1N
Agent: Cl
Agent: II
Solvent: CCO
Product: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 67 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
A 2 L round bottomed flask equipped with an overhead stirrer, condenser, thermocouple and heating mantle was charged with [2-Amino-4-(3-amino-benzoyl)-phenyl]-acetic acid ethyl ester (48 g, 160.9 mmol) in of ethanol (960 mL). Concentrated HCl(aq) (67 mL) was added dropwise at 21° C. The reaction was exothermic causing a rise in reaction temperature from 21° C. to 28° C. The reaction was heated at 67° C. for 1.5 h and was determined to be complete by thin layer chromatographic analysis (ethylacetate/Hexanes 8:2). The thin layer chromatography plate was viewed with short wavelength UV and I2 stain. Following ethanol evaporation, H2O (480 mL) and saturated NaHCO3(aq) (500 mL) were added to the crude product, and the resulting mixture was stirred for 15 hours. The solids were filtered and washed with H2O (2×200 mL) and methyl t-butyl ether (300 mL). The product was dried at 40° C. for 24 h to afford 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 95% yield (38.6 g, 153.0 mmol).
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[F:16][C:13]([F:15])([F:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)([OH:17])[CH3:1]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At −15° C., 18 ml of a 3 M solution of methylmagnesium chloride in ether were added dropwise to a solution of 5.8 g of 4′-methoxy-2,2,2-trifluoroacetophenone in 35 ml of ether, and the mixture was stirred at room temperature for 5 h. The reaction solution was hydrolysed with aqueous ammonium chloride and extracted with ether. The extract was dried and to give the title product as a colourless oil, which was reacted further without any purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:25]3[C:26]([F:28])=[CH:27][C:22]([Br:21])=[CH:23][N:24]=3)[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(Br)cc3F)CC2)CC1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
2d (0.22 g, 0.71 mmol), 3-bromo-6-chloro-5-fluoro-pyridine (0.2 g, 0.95 mmol) and diisopropylethylamine (0.2 mL, 1.2 mmol) in 2 mL of DMSO were heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash LC(0 to 30% EtOAc+0.1% triethylamine in hexane) to afford 46a (92 mg, 28% yield): HPLC, LC-MS 457.1 (MH).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17](Cl)(=[O:19])=[O:18].Cl.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:47])[CH2:38][O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]3)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:11]1([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[C:10]=1[S:17]([N:42]1[CH2:43][CH2:44][CH2:45][CH2:46][CH:41]1[CH2:40][O:39][CH2:38][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH2:36][CH2:35]1)=[O:47])(=[O:19])=[O:18]
Reactant: CN1CCC(N2CCN(C(=O)COCC3CCCCN3)CC2)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.221 ml, 1.608 mmol) and then 2,4,6-trimethylbenzenesulfonyl chloride (105 mg, 0.482 mmol) were added at 0° C. to a solution of 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride (180 mg, 0.402 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated slowly to room temperature, stirred for 15 h at that temperature and then refluxed for 1 h. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the mixture, and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (300:100:5). Yield: 90 mg (43%), yellow oil; MS, m/z 520.3 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1>C(Cl)(Cl)Cl>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20]
Reactant: CC1CCCCN1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Solvent: ClC(Cl)Cl
Product: CC1CCCCN1c1c(-c2c(F)cc(F)cc2F)c(Cl)nc2nccn12
Temperature: 80 °C
Yield: 39.8 %

Procedure:
A mixture of 0.63 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-imidazo[1,2-a]pyrimidine, 0.79 g of 2-methylpiperidine and 2 ml of chloroform was heated at 80° C. for one hour. The reaction mixture was allowed to cool and subjected to silica gel column chromatography to give 0.30 g of 5-(2-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][C:19]=2[CH:20]=1)=[O:13])C.[Li+].[OH-]>C1COCC1>[C:25]1([C:22]2[CH:23]=[CH:24][C:18]3[O:17][C:16]([CH2:15][O:14][C:12]([NH:11][C:6]4[CH:7]=[N:8][CH:9]=[CH:10][C:5]=4[C:4]([OH:31])=[O:3])=[O:13])=[CH:20][C:19]=3[CH:21]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccncc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cnccc1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Reaction time: 3 h
Yield: 51.5 %

Procedure:
To a solution of 3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-isonicotinic acid ethyl ester (0.150 g, 0.36 mmol) in THF (3 ml) was added at room temperature 1.0M LiOH (0.72 mL, 0.72 mmol) and the mixture was stirred for 3 h. The solvent was evaporated, water was added, followed by 2N HCl to adjust the pH to 1-2, and the product was extracted with EtOAc. The extract was washed with water, then brine, and dried over magnesium sulfate and concentrated to dryness. Purification by crystallization gave 0.072 g of 3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-isonicotinic acid as a white solid, mp 235.7-238.9° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([C:31]#[N:32])[N:13]=2)[N:3]=1
Reactant: [C-]#N
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C#N)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 750 mg, 1.77 mmol, 1.0 eq) and sodium cyanide (173 mg, 3.54 mmol, 2.0 eq) in DMSO (5.3 mL) was allowed to stir at room temperature for 1 hour. The reaction appeared complete by LCMS. Water was added to the reaction mixture and the resulting precipitate was isolated by suction filtration and washed with water. The precipitate was then triturated with ethyl acetate to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidine-2-carbonitrile (21) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.69 (ddd, 1H, J=6.3, 5.1, 1.8 Hz), 7.37-7.18 (m, 3H), 3.85 (s, 3H), 3.03 (ddd, 1H, J=9.3, 4.5, 3.9 Hz), 2.94 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H), 2.13-1.98 (m, 2H). LRMS m/z (M+H) 371.0 found, 371.2 required. m.p. 229-231° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(O)C>[ClH:31].[ClH:31].[ClH:31].[N:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(NCCN1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.60 g (8.38 mM) of N-[2-(4-tert-butoxycarbonyl-1-piperazinyl)ethan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 100 ml of ethanol was added 3.4 ml (41.90 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for one hour. The resulting crystals were collected by filtration and rinsed with small amounts of ethanol and ether to provide the title compound. Yield 3.36 g (91.4%, orange-colored crystals).