Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:29][NH2:30].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)=[N:30][NH:29][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2
Solvent: CCO
Solvent: O
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methoxy-4-nitrobenzoyl)phenylacetate (1.2 g, 3.2 mmol) and hydrazine hydrate (0.6 mL, 11 mmol) in ethanol (15 mL) as a yellow solid (0.53 g, 1.5 mmol, 47%), mp: 267°-269° C. 1H NMR (CDCl3) 8.60 (s, 1H), 7.86 (d, J=8.5, 1H), 7.49 (d, J=1.5, 1H), 7.13 (dd, J=8.5, 1.5, 1H), 6.85 (s, 1H), 6.59 (s, 1H), 6.06 (s, 2H), 4.01 (s, 3H), 3.48 (s, 2H). Anal. Calcd. for C17H13N3O6 : C, 57.47; H, 3.69; N, 11.83. Found: C, 57.07; H, 3.42; N, 12.01.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH3:13].CCO>>[NH2:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: N
Solvent: CCO
Product: NCc1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred solution of NH3/EtOH (170 mL) was added (4-Bromomethyl-phenyl)-acetic acid (1.61 g, 7.01 mmol). The resultant solution was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and redissolved with anhydrous THF (10 mL). To the solution, BH3.Me2S was added, and the mixture was stirred for 1 h at 70° C., and at room temperature for 2 d. The reaction was concentrated in vacuo, 6 N HCl (10 mL) was added, and the mixture was stirred at 70° C. for 1 h. Water (20 mL) was added, and it was neutralized with 1 N NaOH to pH˜7. The solution was concentrated to dryness under high vacuum, washed with MeOH/CH2Cl2, and filtered. The crude product was purified by flash chromatography on silica gel (5:3:92 CH3OH—NH3 H2O—CH2Cl2) to afford the title compound (820 mg, 77%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (133 mg, 56%). MS (ISP) 477.1 [(M+H)+]; mp 218-220° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH:19]#[C:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:17]
Reactant: C#CC(O)CCC
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: CCCC(O)C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 (3 g, 9.2 mmol) with hex-1-yn-3-ol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxyhex-1-ynyl)phenyl)propyl)acetamide as yellow oil. Yield (2.31 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.26-7.38 (m, 3H), 4.86 (m, 1H), 4.61 (dd, J=2.0, 5.6 Hz, 1H), 3.67-3.71 (m, 1H), 3.37-3.46 (m, 1H), 2.38 (d, J=2.0 Hz, 1H), 1.95-1.99 (m, 2H), 1.75-1.88 (m, 2H), 1.53-1.57 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[C:28]([O:31][CH2:32][CH2:33][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCOC(C)=O)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to that of Example 51, by reaction of 400 mg (0.93 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate with 334 mg (2.2 mmol) of 2-bromoethyl acetate and 257 mg of potassium carbonate in MEK (10 ml), 333 mg (69%) of a yellow oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OC1CCc2c(Br)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of the crude 4-bromo-1-indanol (1.02 g) in dimethylformamide (10 ml) were added at an ice temperature imidazole (0.645 g) and tert-butyldimethylsilyl chloride (0.857 g). The reaction mixture was stirred at the same temperature overnight, poured into a saturated aqueous saline solution and extracted with ether. The organic layer was washed with a saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (1.6 g) was purified by chromatography on a silica gel column to give the title compound (1.51 g).
Reaction SMILES: [Cl:1][CH2:2]/[C:3](/[NH:12][C:13]([NH2:15])=[O:14])=[C:4](\[C:10]#[N:11])/[C:5](OCC)=[O:6].Cl>[OH-].[Na+]>[C:10]([C:4]1[C:5](=[O:6])[NH:15][C:13](=[O:14])[NH:12][C:3]=1[CH2:2][Cl:1])#[N:11]
Reactant: CCOC(=O)/C(C#N)=C(/CCl)NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(CCl)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
Dissolved in 17 ml of a 2 N aqueous solution of sodium hydroxide were 3.88 g of the ethyl 4-chloro-2-cyano-ureidocrotonate (22) obtained in Referential Example 5. The resulting mixture was stirred at room temperature for 1 hour and under ice cooling, was neutralized with 2 N hydrochloric acid. A crystallized matter was collected by filtration, whereby 1.16 g of the title compound were obtained (yield: 37%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[O:11][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2-(tert-butyldimethylsilanyloxy)-1-phenylethanol (0.73 g, 2.9 mmol) and 3,4-dihydro-2H pyran (486 mg, 5.78 mmol) in dichloromethane (30 ml) was added p-toluenesulfonic acid monohydrate (50 mg). The mixture was stirred at room temperature for 12 hours and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to give tert-butyldimethyl[2-phenyl-2-(tetrahydropyran-2-yl-oxy)ethoxy]silane (0.86 g, 2.9 mmol, >99%) as a colorless oil.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[C:1]([NH:5][S:6]([CH2:9][CH:10]([NH2:25])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)c1ccc(F)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)CC(N)c1ccc(F)cc1

Procedure:
A solution of 0.66 g of N-(tert-butyl)-2-(4-fluorophenyl)-2-oxoethanesulfonamide, 1.85 g of ammonium acetate and 0.17 g of sodium cyanoborohydride in 12 ml of methanol was stirred at 60° C. for 17 hours. After the removal of the solvent under reduced pressure, the residue was taken up in 50 ml of ethyl acetate and washed twice with 30 ml of 0.5 N aqueous sodium hydroxide solution and 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][C:25]([OH:27])=O)[C:18]=3[CH:28]=1)=[O:12])=[CH:5]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[O:27]=[C:25]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:24][N:19]1[C:18]2[CH:28]=[C:14]([NH:13][C:11]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[O:12])[CH:15]=[CH:16][C:17]=2[O:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)N(CC(=O)N1CCCC1)CCCO2)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid (80 mg) and pyrrolidine (14.2 mg) were dissolved in anhydrous THF. To that solution was added BOP and the resulting mixture treated with triethylamine (40.5 mg). The reaction was stirred overnight at room temperature. The reaction was evaportated and the crude product purified by TLC using EtOAc as solvent to yield 68 mg of the product. LCMS: AP+ 453/455.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[CH2:24][CH2:25]OC.P(Br)(Br)[Br:29]>C(Cl)(Cl)Cl>[Br:29][CH2:25][CH2:24][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: COCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Solvent: ClC(Cl)Cl
Product: Cc1c(CCBr)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 1-(4-fluoro)phenyl-3-(2-hydroxyethyl)-2-methyl-5-[4-methylsulphonyl)phenyl]-1H-pyrrole (example 23) (1.30 mmol) in CHCl3, PBr3 (5 mL) was added. The resulting mixture was stirred at r.t. for 2 h. The solution was cooled, the reaction quenched with ice, and the mixture basified with a saturated Na2CO3 solution and then extracted with CH2Cl2. The organic phase was washed to neutrality with brine, dried and evaporated under reduced pressure. The residue, purified by flash-chromatography (EtOAc/hexane 4:6 v/v), gave the expected compound as yellow oil (yield 36%) 1H-NMR (CDCl3) δ ppm: 2.03 (s, 3H), 2.96-3.06 (m, 5H), 3.52 (t, 2H, J=7.5), 6.41 (s, 1H), 7.05-7.15 (m, 6H), 7.61-7.66 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OCCCc1cccc2cc[nH]c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
To a solution of 7-hydroxypropyl-1H-indole (4.45 g, 25.4 mmol) in methylene chloride (50 mL), was added imidazole (2.31 g, 34.0 mmol), followed by tert-butyldimethylsilyl chloride (5.44 g, 36.1 mmol). The reaction mixture was stirred at room temperature for 12 h, filtered and concentrated to a brown oil. Flash chromatography (SiO2, 10% EtOAc/hexanes) gave the title compound (4.9 g, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 9.38 (bs, 1H), 7.54 (m, 1H), 7.22 (m, 1H), 7.18–6.06 (m, 2H), 6.60 (m, 1H), 3.71 (m, 2H), 3.07 (m, 2H), 1.98 (m, 2H), 1.03 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [CH:1]1[C:6](C2C=C[C:10]3[C:13]([O:15][C:16](=[O:17])[C:9]=3C=2)=[O:14])=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O.C(OC(=O)C)(=O)C.CC([N:33](C)C)=O>>[C:13]([O:15][C:16](=[O:17])[CH3:9])(=[O:14])[CH3:10].[N:33]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[CH3:5]
Reactant: CC(=O)N(C)C
Reactant: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccn1
Reaction time: 4 h

Procedure:
Under ambient temperature, nitrogen gas is fed into a 500-ml three-necked flask polymerization vessel. All reactions are performed under a nitrogen environment. About 160 g of DMAC used as solvent is added into the flask. About 18.77 g (0.059 mole) of TMFB are dissolved into the DMAC. After the TMFB is completely dissolved in the DMAC solvent, about 13.35 g (0.045 moles) of BPDA and about 7.87 g (0.015 moles) of BPADA are added into the liquid solution, which is then continuously agitated for about 4 hours for forming a PAA solution with a viscosity of about 150,000 cP. The PAA solution is mixed with a dehydrant acetic anhydride and a catalyst picoline with a PAA:acetic anhydride:picoline molar ratio of about 1:2:1 to obtain a precursor solution. A polyimide film is casted in the same manner as Example 1.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2C(=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2CCC)=O.CO[C:20]1[CH:21]=[CH:22][C:23](/[CH:32]=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=[CH:24][C:25]=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:32]\[C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:5][CH2:4][CH2:3][CH2:12][CH3:11])/[C:34](=[O:35])[N:36]=1
Reactant: CCCc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-propyl-quinoline-3-carbonitrile (example 72c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-pentyl-quinoline-3-carbonitrile. LC-MS m/e 351 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[N:30]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Product: Cn1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 2.1 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a white powder. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 3) tR0.98 min, m/z=464 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.90 (m, 2H) 2.85-3.00 (m, 1H) 3.06-3.26 (m, 3H) 3.59 (s, 3H) 4.19 (br. s, 1H) 4.87 (d, J=2.74 Hz, 1H) 6.39 (s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.50 (dd, J=1.76, 0.98 Hz, 1H) 7.84 (d, J=8.60 Hz, 2H) 8.01 (d, J=2.74 Hz, 1H) 8.78 (dd, J=2.54, 0.98 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccn1
Product: CN(C)C=CC(=O)c1ccccn1

Procedure:
A mixture of 25 g. of 2-acetylpyridine and 35 ml. of N,N-dimethylformamide dimethylacetal is refluxed for 16 hours. The mixture is cooled and filtered to give 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one as crystals, m.p. 127°-130° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]([C:14]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[C:7]([Br:6])[CH:15]=1)=[O:17]
Reactant: O=C(O)c1cc(Br)c2cc[nH]c2c1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCO)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
3-Aminopropanol (1.36 g, 18.1 mmol) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (4.35 g, 18.1 mmol), triethylamine (4.60 mL, 45.3 mmol), and O-benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (6.87 g, 18.1 mmol) in DMF (40 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to yield 3.0 g (56%) of 4-bromo-1H-indole-6-carboxylic acid (3-hydroxy-propyl)-amide. Mass spectrum (LCMS, ESI pos.): Calcd for C12H13BrN2O2 296.02. Found 296.9; (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)(=[O:25])=[O:24])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1cc(Cl)ccc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 49% yield, starting from 2-amino-5-chlorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CNCC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.0-3.8 (m, 14H), 2.98 (s, 3H), 2.2 (m, 1H), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13].[CH2:16](I)[CH3:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][N:10]=[C:9]1[S:15][CH2:16][CH3:17]
Reactant: CCI
Reactant: NC(=O)CNC(=S)Nc1ccccc1Cl
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccccc1Cl
Yield: 65.9 %

Procedure:
A mixture of 2-[3-(2-chlorophenyl)-thioureido]-acetamide (12.2 g), ethyl iodide (15.6 g), and ethanol (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with water (2×300 mL). The organic phase was then extracted with 2N HCl (2×500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO4 then evaporated to dryness. The residue was dissolved in ethanol and the solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was crystallized from ethyl acetate to give the hydrochloride salt of the title compound (8.4 g) as an off-white solid, m.p. 149°-150° C. (dec.). Anal. Calcd. for. C11H11Cl N2O S. HCl: C, 45.37; H, 4.15; N, 9.62. Found: C, 44.97; H, 4.06; N, 9.51. Mass spectrum (EI, M.+) m/z 254/256. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.69 (m, 1H), 7.50-7.58 (m, 3H), 4.45 (q, 2H), 3.11-3.17 (m, 2H), and 1.27 ppm (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:22]=[N+:23]=[N-:24])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.47 g, 1.5 mmol) in dry N,N-dimethylformamide (5 ml), sodium azide (0.20 g, 3.0 mmol) was added and the mixture was stirred at 100-110° C. for 4 hours. The solvent was removed and the residue washed with water to leave 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a crystalline solid (0.36 g, 75%), m.p. decomposed at 200° C.; λmax (MeOH) 272 (ε 8,210) and 301 (ε 10,100) nm; νmax (KBr) 1670, 1625, and 1560 cm−1; δH (CDCl3—CD3OD) 1.44 (6H, s, C(CH3)2), 1.6-2.2 (3H, m, CHCH2CH2), 3.5-3.8 (2H, dd (ABX), J 7 Hz and J 11 Hz, 2×Hax), 3.85-4.15 (2H, dd (ABX), J 4 Hz and J 11 Hz, 2×Heq), 4.29 (2H, t, J 7 Hz, CH2N), and 7.93 (1H, s, 8-H) (Found: C, 48.96; H, 5.66; N, 35.15%; M+ 318.1553. C13H18N8O2 requires C, 49.05; H, 5.07; N, 35.20%; M+ 318.1546).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].[CH3:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21](Br)=[CH:20][C:18]=2[N:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][C:7]=1[C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([CH3:14])=[N:19][C:18]=2[CH:20]=1
Reactant: Cc1nc2cc(Br)ccc2o1
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)cc1-c1ccc2oc(C)nc2c1
Yield: 89.6 %

Procedure:
A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 2-methyl-5-bromobenzoxazole (1 g, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd(Ph3)4 (55 mg, 0.047 mmol). The mixture was refluxed for 20 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4) to give 1.13 g of title compound.