Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]([F:19])([F:18])[C:14](Br)(Br)[Br:15]>>[Br:15][C:14]([C:13]([F:19])([F:18])[F:12])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: FC(F)(F)C(Br)(Br)Br
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(C=C(Br)C(F)(F)F)cc1

Procedure:
The product was prepared from 4-nitro-benzaldehyde and from 1,1,1-trifluoro-tribromoethane (CF3 --CBr3) by operating according to the process of example 1. The obtained product has:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH3:9][CH2:8][CH2:7][C@H:6]([NH:10][C@H:11]([C:13]([N:10]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][C@H:24]2[C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:23]2)=[O:15])[CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: CCCCCC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reaction time: 1.5 h

Procedure:
To a slurry of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine (1.5 g, 0.0069 moles, as obtained in Step-IV, Method-I and Step-II, Method-II) in n-hexane (10 ml) was purged dry hydrogen chloride gas at 25-30° C. under agitation. To this was added finely ground phosphorous pentachloride (1.8 g, 0.0086 moles) in four lots, each after an interval of 10 mns. After the complete addition the reaction mixture was agitated for 1.5 hrs. The solid precipitated was filtered, washed with hexane to give 1.88 g of the title compound (I).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.Cl>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCc1cnc2ccccc2c1Cl
Agent: Cl
Product: CCCCc1cnc2ccccc2c1Nc1ccc(C(=O)O)cc1
Yield: 29 %

Procedure:
0.520 g of the product of Step F of Example 1 and 0.390 g of 4-amino benzoic acid were introduced into 6 ml of 2N hydrochloric acid and the solution was refluxed for 63 hours. The precipitate was filtered off, washed with water and taken up in 10 ml of 2N sodium hydroxide in 40 ml of water, then washed with ethyl acetate. The aqueous phase was taken up in acetic acid and the precipitate was filtered, washed with water, separated out and taken up in ether. After drying, 220 mg of the expected product melting at 276° C. were obtained.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[F:16]C1C=CC([N+]([O-])=O)=CC=1>>[CH:5]12[N:8]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][C:15]=3[F:16])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: Nc1ccc(N2C3CCCC2CC3)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(N2C3CCCC2CC3)c(F)c1

Procedure:
The title compound was prepared using the procedure as described for the preparation of the product of Example 6B, substituting 3,4-difluoronitrobenzene for 4-fluoronitrobenzene 1H NMR (300 MHz, CDCl3) δ 6.69 (m, 1H), 6.40 (m, 2H), 4.00 (brs, 2H), 3.42 (brs, 2H), 1.86-2.03 (m, 4H), 1.65-1.77 (m, 3H), 1.32-1.57 (m, 3H).
Reaction SMILES: [S:1]1(=[O:7])C=C[C:3](=[O:6])[NH:2]1.S(Cl)(Cl)(=O)=O.[CH2:13]([Cl:16])[CH2:14][Cl:15]>>[Cl:15][CH:14]1[CH:13]([Cl:16])[S:1](=[O:7])[NH:2][C:3]1=[O:6]
Reactant: ClCCCl
Reactant: O=C1C=CS(=O)N1
Solvent: O=S(=O)(Cl)Cl
Product: O=C1NS(=O)C(Cl)C1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2g. (0.02 mole) of 4-isothiazolin-3-one 1-oxide in 80 ml. ethylene dichloride (EDC) is added 2.4g. (0.02 mole) of sulfuryl chloride. The mixture is stirred at room temperature overnight. The white solid which forms is filtered, washed with EDC and air dried to yield 2.0g. (52%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][CH2:5]1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40 mg (62%) the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:24]1[C:29]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:28][C:27]([NH2:41])=[C:26]([N+:42]([O-:44])=[O:43])[CH:25]=1>C(COC)OC>[NH2:41][C:27]1[C:26]([N+:42]([O-:44])=[O:43])=[CH:25][C:24]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
7.9 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 1.8 g of dichlorobistriphenylphosphine palladium, 50 ml of aqueous saturated sodium carbonate solution and 50 ml of water were added in order to a dimethoxyethane (100 ml) solution of 10.3 g of 4-bromo-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine, and the reaction liquid was stirred in a nitrogen atmosphere at 80° C. for 1 hour. After cooled, the reaction liquid was filtered through Celite, the filtrate was diluted with ethyl acetate, washed with water and saturated saline in order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH:21]([CH3:25])[CH:22]([OH:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].[CH3:42]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH:21]([CH3:25])[C:22]([OH:24])([CH3:42])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)O)CC2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.66 g), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.76 g) and acetonitrile (20 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.4 mL) was added at 0° C. The reaction mixture was warmed to 0° C., and stirred for 6 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.CS(O)(=O)=O.[OH-].[Na+].C(OC)(C)(C)C>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][C:11]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[S:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(SCC(=O)CCc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc2c(CCc3ccccc3)csc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Step C (8.495 grams), dissolved in dry CH2Cl2 (85 mL) was added dropwise to a 0° C. CH2Cl2 solution (34mL) of methanesulfonic acid (17 mL). The reaction was kept at 0° C. for 20 minutes, then briefly warmed to ambient temperature. The reaction was rapidly poured into a vigorously stirred cold mixture of excess 5N NaOH and methyl tert-butyl ether. The organic was dried over magnesium sulfate and filtered. Concentration and chromatography over silica gel (5:1 hex/CH2Cl2) gave the title compound as a clear oil.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[N:39]1([C:36]2[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]3[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=4)=[O:30])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCCC2)nc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 87 %

Procedure:
0.28 ml (1.68 mmol) of diethyl cyanophosphonate is added, dropwise, at 20° C. under argon, to a solution of 0.402 g (1.4 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and of 0.274 g (1.68 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine (WO 02/48152) in 10 ml of dry dimethylformamide. The mixture is stirred for ten minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours, concentrated under reduced pressure, and then taken up with 50 ml of ethyl acetate. This solution is then successfully washed with three times 20 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained is triturated in isopropylether under hot conditions. 0.527 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].Cl[CH2:39][S:40][CH3:41]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:39][S:40][CH3:41])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCN1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C)CC1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (200 mg, 0.38 mmol, 1.00 equiv), tetrahydrofuran (10 mL), sodium hydride (30 mg, 0.75 mmol, 2.00 equiv, 60%), chloro(methylsulfanyl)methane (149 mg, 1.54 mmol, 4.00 equiv). The resulting solution was stirred for 1 h at 50° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel TLC-plate with ethyl acetate/petroleum ether (1/1). This resulted in 60 mg (27%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-[(methylsulfanyl)methyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:11][OH:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([C:11]([OH:20])=[O:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(CO)nc2cc(C(C)=O)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCCn1c(C(=O)O)nc2cc(C(C)=O)ccc21

Procedure:
In a manner analogous to that described in Example 12, 4.9 g of 5-acetyl-1-n-butyl-benzimidazole-2-methanol can be oxidised with 4.5 g of potassium permanganate to give 5-acetyl-1-n-butyl-benzimidazole-2-carboxylic acid with a melting point >75° (decomposition).
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)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>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yne (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>ClCl>[CH3:16][C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])([CH3:17])[CH2:14][OH:15]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: ClCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mmol) in CH2 Cl2 (200 mL) was added rapidly dropwise to an ice water-cooled solution of 2-amino-2-methyl-1-propanol (63.1 g, 708 mmol) in CH2 Cl2 (400 mL). The resulting mixture was stirred at RT and monitored to completion by GLC, then was extracted twice with 10% HCl and once with sat aq NaHCO3. The organic phase was dried (MgSO4), and concentrated to afford 61.9 g N-(1,1-dimethyl-2-hydroxyethyl)-2,6-difluorobenzamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[C:5](Br)=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].[CH2:15]([C:18]1[S:19][C:20]([Sn](C)(C)C)=[CH:21][CH:22]=1)[CH2:16][CH3:17]>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>[CH3:14][S:12]([C:3]1[CH:4]=[C:5]([C:20]2[S:19][C:18]([CH2:15][CH2:16][CH3:17])=[CH:22][CH:21]=2)[C:6]([S:8]([CH3:10])=[O:9])=[CH:7][C:2]=1[C:20]1[S:19][C:18]([CH2:15][CH2:16][CH3:17])=[CH:22][CH:21]=1)=[O:13]
Reactant: CS(=O)c1cc(Br)c(S(C)=O)cc1Br
Reactant: CCCc1ccc([Sn](C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCC)s3)cc2S(C)=O)s1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
1,4-dibromo-2,5-bis(methylsulfinyl)benzene 3 (2.60 g, 7.21 mmol) was added to a solution of 2-propyl-5-trimethylstannylthiophene (5.0 g, 17.3 mmol) in anhydrous Toulene (48 mL), and the resulting mixture was purged with nitrogen for 30 min. Pd(PPh3)4 (0.833 g, 0.072 mmol) was then added, and the reaction mixture was heated to 100° C. overnight. Excess Toulene was removed under high vacuum, and the residue was dissolved in ethyl acetate and treated with 10% aqueous KF. The mixture was filtered through a pad of Celite. The filtrate was dried over Mg2SO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (silica gel, eluent:hexane/EA) 2:1) to afford 2.63 g (81%) of 2c.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=O>>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CN(C)C=CC(=O)c1ccncc1
Product: O=C(c1ccccc1)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
Following the general procedure of Example 8 and reacting (3-amino-1H-pyrazol-4-yl)phenyl-methanone with 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one gave the desired product, mp 185°-186° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[C:26]=2[CH3:37])=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)n(C)c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1,2-Dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=499.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([C:24](=[O:26])[CH3:25])=[C:22]([NH:27][C:28]2[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[N:21]=[CH:20][N:19]=1>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:23]([C:24](=[O:26])[CH3:25])=[C:22]([NH:27][C:28]3[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.2 mmol, 633 mg) and sodium hydride (3.2 mmol, 76 mg) were dissolved in N,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at room temperature. Subsequently, compound 1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone (0.63 mmol, 207 mg) was added. The reaction was stirred at 70° C. for 30 minutes. Progress of the reaction was monitored by thin layer chromatography and LCMS. Sodium hydride was carefully quenched with water and the desired compound was extracted with ethyl acetate. Organic solvents were evaporated in vacuo and purified by flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes) to afford Compound A37 as a yellow solid (156 mg, 50%). 1H NMR (400 MHz, CDCl3) δ (ppm): 12.19 (s, 1H), 8.95 (s, 1H), 8.56 (d, 1H), 8.44 (s, 1H), 8.07 (d, 1H), 5.56 (h, 1H), 3.82 (m, 2H), 3.31 (m, 2H), 3.23 (s, 3H), 2.70 (s, 3H), 2.11 (m, 2H), 1.85 (m, 2H), 1.48 (s, 9H). LCMS (ESI), m/z 492.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:21])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(N(C)C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)C=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(4-methoxyphenyl)-3-(4-dimethylaminophenyl)-1-oxo-prop-2-ene (14.1 g, 0.05 mol) was dispersed in methanol (100 ml). Sodium borohydride (5.6 g, 0.15 mol) was added slowly at ambient temperature under vigorous stirring. After completion of the addition of sodium borohydride the reaction mixture was kept stirred at ambient temperature for 5 hours. When the reaction was complete, the reaction mixture was poured into water (500 ml), and extracted with toluene. The toluene was removed using a rotary evaporator leaving an oily residue. The crude product was crystallized from methanol to give 1-(4-methoxyphenyl)-3-(4-dimethylaminophenyl)prop-2-en-1-ol as a white coloured solid in a yield of 4.0 g (28.3% of theory) with a melting point of 137-148° C.