Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(N(CC)CC)C>[C:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccc(Br)s1
Reactant: C#CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1ccc(C=O)s1
Temperature: 105 °C
Yield: 78.1 %

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (8.5 g, 0.05 mole) was combined with 1-octyne (11.0 g, 0.1 mole) and triethylamine (200 ml). The mixture was degassed under argon and cuprous iodide (950 mg, 10 mole %) and tetrakis (triphenylphosphine) palladium (1.75 g, 5 mole %) were added. The mixture was heated at 105° C. for twenty hours under argon and cooled. The triethylamine was evaporated and the residue purified by chromatography on silica eluting with hexane/chloroform (3:1) to yield the title compound 8.6 g (83.7%) as a yellow oil. mp 130° C., νmax (film) 3320, 2225, 1675, 1050, 805, 780, 675; δ(CDCl3) 0.87(3H, t, J=6 Hz), 1.33(8H, m), 2.33(2H, t, J=6 Hz), 7.13(1H, d, J=6 Hz), 7.65(1H, d, J=6 Hz), 9.87(1H, s).
Reaction SMILES: Cl[C:2]1[C:6]2[N:7]([C:17](=[O:34])[CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:21][CH2:20]3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:35])[CH:3]=1.C.[OH-].[Na+].C(#N)C>C(O)C.[Pd]>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]3[N:4]([CH3:35])[CH:3]=[CH:2][C:6]2=3)=[O:34])[CH2:20][CH2:21]1)[CH3:33]
Reactant: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2c(Cl)cn3C)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2ccn3C)CC1
Reaction time: 20 h

Procedure:
3.957 g (8.14 millimol) of 3-chloro-4-[[4-[4-(diethylamino)-butyl]-1-piperidinyl]acetyl ]-1-methyl-1,4,9,10-tetrahydropyr rolo[3,2-b][1,5]benzodiazepin- 10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal (20%), hydrogenated for 20 hours under a hydrogen pressure of 50 bar and at a temperature of 40° C. The catalyst was filtered off, the filtrate was concentrated by evaporation in vacuo, the crystalline hydrochloride was taken up in 20 ml of water, the solution obtained was made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated down and the residue remaining was recrystallised. 1 g (26.3% of theory) of colourless crystals were obtained, m.p. 198° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccncc3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9]([NH2:18])=[N:8][C:6]=2[N:7]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[C:9]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3ccncc3)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1ccncc1

Procedure:
Following the procedure of Example 2, 0.30 g of 2,7-diamino-6-(4-pyridyl)-pyrido[2,3-d]pyrimidine from Example 109 was reacted with 0.154 mL of tert-butyl isocyanate. The product was purified by medium pressure chromatography using silica gel and eluting with 90:10:1 EtOAc:MeOH:TEA, to afford the title compound, mp >350° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 338 (MH+ +1, 6), 339 (MH+ +2, 1), 84 (100).
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([C:11](=O)[CH3:12])=[C:4]([I:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1.Cl>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([CH2:11][CH3:12])=[C:4]([I:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1
Reactant: CCc1c(I)c(C(C)=O)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: Cl
Product: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17). 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carboxylic acid (18)
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][C:35](=[O:37])[CH3:36])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2, Example 18), 0.027 mL (0.28 mmol) of acetic anhydride, 0.046 mL of pyridine and 3.4 mg of DMAP in 2 mL of THF was stirred at rt for 18 h. The reaction mixture was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 15:15:1) to give the title compound as white solid. 1H NMR (CDCl3) δ (key peaks) 7.89-7.90 (m, 3H), 7.47-7.54 (m, 4H), 7.19 and 7.09 (d of d, 2H, J=6.0, 8.5 Hz), 6.99 and 6.94 (t, 2H, J=8.5 Hz), 5.04-5.20 (m, 1H1), 1.34 and 1.09 (d, 3H, J=6.5 Hz), Mass Spectrum (ESI) m/e=503 (M+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[OH:3][N:1]=[C:8]([C:7]([CH2:6][Br:5])=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N[C@H:16](C(O)=O)CCSC>COCCOC>[CH3:16][C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: O=C1CCCC1c1ccccc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2ccccc2)CCCC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a slurry of 60% NaH (125 mg, 3.12 mmol) in DME (3571 μL) at 0° C. was added 2-phenylcyclopentanone (500 mg, 3.12 mmol). After stirring for 1 h, Met (898 μL, 14.36 mmol) was added, and the solution heated to reflux for 2 h. The reaction was poured onto ice and extracted 3 times into Et20. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Applied to Silica gel and eluted with an EtOAc/Hex gradient to afford 2-methyl-2-phenylcyclopentanone (401.7 mg, 2.305 mmol, 73.9% yield). LC-MS (M+H)+=175.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.37 (4H, m), 7.20-7.24 (1H, m), 2.54 (1H, dt, J=12.51, 6.26 Hz), 2.34 (2H, t, J=7.63 Hz), 1.82-2.05 (3H, m), 1.38 (3H, s).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[C:22]=2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]3[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:10]=[CH:11][CH:12]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([S:13][C:14]2[N:15]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:17]3[C:22]=2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]3[CH2:26][CH:27]([CH3:28])[CH3:29])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Sc2c3c(=O)n(C)c(=O)n(CC(C)C)c3cn2Cc2cccc3ccccc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(O)c3)n(Cc3cccc4ccccc34)cc21
Reaction time: 6 h
Yield: 61.7 %

Procedure:
A solution of boron tribromide in dichloromethane (1M, 3 ml) was added to a solution of 5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (200 mg) (compound of Example 23) in dichloromethane (20 ml) at ambient temperature. After 6 hours, water (10 ml) was added carefully and the reaction mixture was partitioned between dichloromethane and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by chromatography on silica gel, eluting with isohexane/ethyl acetate (2:1 to 1:1) followed by recrystallisation from isohexane/ethyl acetate (3:1), gave the title compound (120 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[Br:8][C:9]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Br:8][C:9]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:2]2[S:6][C:5]([NH2:7])=[N:4][N:3]=2)[CH2:13]1
Reactant: Fc1ccc(Br)c(O[C@H]2CCNC2)c1
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)s1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (1 g, 5.6 mmol), (3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidine (1.6 g, 6.1 mmol) and sodium carbonate (1.2 g, 11 mmol) in EtOH (11 mL) was degassed with nitrogen for 5 mins. The mixture was then heated at 90° C. for 3 h. The mixture was then cooled to room temperature and filtered. The solvent was evaporated and diluted with water (50 mL). The solid precipitate was filtered and washed with water followed by Et2O to afford the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(OCC)(=[O:12])C>O.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:9])=[O:12])=[N:6][CH:7]=1
Reactant: CSc1ccc(Br)cn1
Reactant: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NalO4 (0.52 g) dissolved in water (0.5 mL) was added to a solution of 5-bromo-2-methylsulfanyl-pyridine (0.25 g) in acetic acid (3 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. Then, water and ethyl acetate were added and the mixture was stirred for another 10 min. The organic phase was separated and washed with 10% aqueous Na2S2O3 solution, 10% aqueous K2CO3 solution, and brine. After drying (MgSO4), the solvent was evaporated to afford the title compound. Yield: 0.20 g (72% of theory); Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc(-c2cc(Cl)c3ccc(OC)cc3n2)cc1

Procedure:
The title compound, m. p. 99-101° C., MS: m/e=299 (M+), was prepared from 4-chloro-7-methoxy-quinoline and 4-bromoanisole.
Reaction SMILES: Cl.[CH:2](=[NH:6])[O:3][CH2:4][CH3:5].Cl.[F:8][C:9]([F:13])([F:12])[CH2:10]N.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:8][C:9]([F:13])([F:12])[CH2:10][N:6]=[CH:2][O:3][CH2:4][CH3:5]
Reactant: NCC(F)(F)F
Reactant: CCOC=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC=NCC(F)(F)F
Reaction time: 0.05 h

Procedure:
Ethyl formimidate hydrochloride (0.555 g, 5 mmole), 2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2Cl2 and treated with 2 ml H2O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2Cl2The combined organic phase is dried and the CH2Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. δ1.33 t (CH3CH2); 3.8 q (j=10 c.p.s., CF3CH2) 4.23 q (j=7.5, CH3CH2O); 7.6 S (H-C=N).
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH3:19][C:20](OC(C)=O)=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1.O>[NH4+].[Cl-]>[C:20]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)(=[O:21])[CH3:19]
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OC12CCCCCCCCCC1C(=O)CC(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
2.5 g (10 mmol) of (16) were added to a mixture of 4 g (40 mmol) Ac2O and 95 mg (0.5 mmol) pTsOH.H2O at 0° C. After stirring for 1 hour at 0° C. the mixture was warmed up to room temperature. After 60 minutes, the reaction mixture was poured into 10 g of ice and 10 ml of a saturated aqueous NH4Cl solution. After extraction with 150 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO3 and NaCl solution), dried (Na2SO4) and 1 ml Et3N were added. The solvent was evaporated. Flash chromatography, using SiO2 (300 g) and n-pentane/EtOAc/Et3N=95/4/1 as eluent, afforded 1.31 g (4.4 mmol, yield: 44%) of (28).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)Cl.[C:15](Cl)(=O)[C:16](Cl)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:16][CH2:15]2
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromo-phenyl acetic acid (250.0 g, 1.15 m), methylene chloride (1.5 L), and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0° C. and treated dropwise with oxalyl chloride (156 mL, 1.74 m). The reaction was allowed to reach room temperature and stirred 16 hrs. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under At, fitted with gas inlet tube, overhead stirrer, and digital thermometer was charged with methylene chloride (1.5 L) and AlCl3 (312.0 g, 2.34 m). This suspension was cooled to 0° C. and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1-2 hrs to the vigorously stirred suspension while maintaining the internal temperature at 15° C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 hrs. The mixture was recooled to 0° C. and cautiously quenched slowly with water (1.5 L). The layers were separated, and the aqueous one washed with 500 mL of methylene chloride. The organic portion was washed with 2N aqueous HCl (2×800 mL), brine (400 mL), and saturated aqueous NaHCO3 (2×800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2SO4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0 L of hexane warmed to 50° C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25° C. and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of the compound as a pale yellow solid (88%).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Br:15][C:16]1[C:17]([CH3:25])=[C:18](O)[CH:19]=[C:20]([CH3:23])[C:21]=1[CH3:22].S(=O)(=O)(O)O>O>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[CH:2]([C:6]3[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=3)[C:3](=[O:4])[O:5][C:18]=2[C:17]=1[CH3:25]
Reactant: Cc1cc(O)c(C)c(Br)c1C
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)OC(=O)C2c1ccc(C(C)C)cc1
Temperature: 115 °C
Reaction time: 4 h

Procedure:
To a mixture of hydroxy(4-isopropylphenyl)acetic acid (10.0 g, 46.5 mmol) synthesized in Reference Example 1 and 3-bromo-2,4,5-trimethylphenol synthesized in Reference Example 68 (8.2 g, 42.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature, and the mixture was stirred at 115° C. for 4 hours. The mixture was added to water, which was extracted with diisopropyl ether. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain 6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-1-benzofuran-2 (3H)-one. To a solution of the compound in THF (80 mL) was added lithium aluminum hydride (2.40 g, 63.3 mmol) at 0° C., and the mixture was heated under reflux for 1 hour. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 15.5 g (yield 97%) of the title compound. Melting point: 96-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16](=[O:23])[NH:17][C:18]1([C:21]#[N:22])[CH2:20][CH2:19]1)=[O:5])[CH3:2].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][C@H:7]1[C:16](=[O:23])[NH:17][C:18]1([C:21]#[N:22])[CH2:19][CH2:20]1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Product: CCOC(=O)[C@@H]1C[C@H](Sc2ccccc2)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mixture of (1R,2R,4R) and (1R,2R,4S)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester from step 3 with thiophenol performed in analogy to example 1, step 5, yielded a crude material which was purified on silica using n-heptane/EtOAc (3:2) to give in the first fraction the desired (1R,2R,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-phenylsulfanyl-cyclopentanecarboxylic acid ethyl ester as a colorless oil. MS: 359.2 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
A mixture of 3 g of adamantan-1-ylmethanol and 5 ml of triethylamine in 50 ml of DCM is cooled to 0° C., 2 ml of methanesulfonyl chloride are added dropwise, and the mixture is left to stir while allowing the temperature to return to AT. A mixture of water/ice is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 2 g of the expected compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Cl-].[C:11]1([P+:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)CC2C=NC=CC=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl-:1].[C:31]1([P+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:2][C:3]2[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Prepared from 5-chlormethyl-2-methyl-pyridine (Arch. Pharm. 1975, 308, 359) as described in expl. 1a): 1H-NMR (DMSO-d6) inter alia 5.24 (d, J=15.6 Hz, H2C), 2.38 (s H3C).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCc1cccc(F)c1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCc2cccc(F)c2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-fluorophenyl)ethanamine (300 mg, 2.16 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (160 mg) as a yellow solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.86-2.90 (m, 2H), 3.51-3.56 (m, 2H), 5.39 (s, 2H), 6.04 (s, 2H), 6.29 (s, 1H), 6.97-7.43 (m, 6H), 7.70 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).