Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4]1.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+].[C:33](=[O:36])([O-:35])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:5]([OH:30])(=[O:4])/[CH:6]=[CH:8]\[C:33]([OH:35])=[O:36].[C:8]1([CH:6]2[CH2:5][O:4][CH:3]([CH2:2][N:27]3[CH2:26][CH2:25][C:24]4([N:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:21][NH:22][C:23]4=[O:30])[CH2:29][CH2:28]3)[CH2:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: BrCC1CC(c2ccccc2)CO1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)/C=C\C(=O)O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CC(c3ccccc3)CO1)CC2
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 4.0 g of 2-bromomethyl-4-phenyltetrahydrofuran, 3.83 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 2.48 g of sodium iodide and 2.3 g of potassium carbonate in 50 ml of dimethylformamide is heated with stirring at 60° C. for 24 hours. The reaction mixture is then poured into 200 ml of water, and 50 ml of ethyl acetate is added thereto. The mixture is stirred under ice-cooling. The crystals precipitated are collected by filtration, treated with maleic acid and recrystallized from ethanol to give 8-(4-phenyl-tetrahydro-2-furylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one maleate, melting at 202°-204° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([NH2:17])=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[N:14]=[N:13]1.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:17][C:16]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[N:13]=[N:14][C:15]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3Cl)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1c(-c2ccc(O)cc2)nnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 3-(2-chloro-4-trifluoromethyl-phenyl)-5-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (3) (1.000 g, 2.7119 mmol) in anhydrous dichloromethane (20 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (11.5497 g, ˜4.36 ml, 46.1023 mmol) in 10 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 10 min stirring, 10% sodium hydroxide solution (20 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×70 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid grey residue (0.800 g, 83% yield, 99.47% pure at HPLC). M.p. 161-162.3° C. LC-ESI-HRMS of [M+H]+ shows 355.0579 Da. Calc. 355.057348 Da, dev. 1.6 ppm.
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:35][C:36]1[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[N:51]=[CH:50][C:49]([O:52][CH2:53][C@@H:54]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH3:55])=[CH:48][C:47]=1[F:64])=O>C(#N)C.O>[F:64][C:47]1[CH:48]=[C:49]([O:52][CH2:53][C@@H:54]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])[CH3:55])[CH:50]=[N:51][C:46]=1[C:44]1[O:35][C:36]2[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:37]=2[N:43]=1
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 210.5 %

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (1.06 g) and potassium carbonate (0.733 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.83 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][C:33]2[C:34](=[O:40])[NH:35][C:36](=[S:39])[NH:37][CH:38]=2)=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][C:33]2[C:34](=[O:40])[N:35]=[C:36]([S:39][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[NH:37][CH:38]=2)=[CH:30][N:31]=1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: FC(F)(F)c1cccc(Oc2ccc(CCl)cc2C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C(F)(F)F)c3)nc2=O)cn1
Yield: 4.4 %

Procedure:
The same procedure as E63 from 4-(chloromethyl)-2-(trifluoromethyl)-1-{[3-(trifluoromethyl)phenyl]oxy}benzene (425 mg, 1.199 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (200 mg, 0.799 mmol) and DIPEA (0.279 mL, 1.598 mmol) in DCE (3.0 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (20 mg, 4.40% yield). LCMS: rt=3.66 min, [M+H+]=569
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1>ClCCl.N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:14]2[CH2:15][CH2:16][CH:12]([OH:18])[CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
A solution of 9.00 g p-toluenesulphonic acid chloride in 30 ml dichloromethane is added dropwise to an ice-cooled solution of 4.97 g cyclopentan-1,3-diol (cis/trans mixture) in 15 ml of pyridine and 10 ml dichloromethane. The solution is stirred for 45 min at 15° C. The solution is diluted with 100 ml dichloromethane, washed twice with 2 N hydrochloric acid and once with water. After drying through sodium sulphate and elimination of the solvent the product is obtained as a brown oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[Br:18]Br>C(Cl)Cl.CO>[Br:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH:12]=1
Reactant: BrBr
Reactant: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Temperature: 25 °C

Procedure:
1-Ethyl-3-(6-methoxy-1,3-benzothiazol-2-yl)urea (1.10 g, 4.38 mmol) was suspended in DCM (50 mL) and MeOH (5 mL). Bromine (0.34 mL, 6.60 mmol) was added and the mixture stirred at rt. The mixture was stirred for a total of 1.5 h then concentrated to dryness under reduced pressure. The desired compound was obtained as an orange solid, 2.17 g, and used without further purification, stating purity as 66 mass % in further reactions. m/z: 329.94/331.91 [M+H]+.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][N:8]1[CH2:29][C:14]23[CH2:15][CH2:16][CH:17]4[CH:26]([CH:13]2[CH2:12][CH2:11][CH:10]3[CH:9]1[CH3:30])[CH2:25][CH:24]=[C:23]1[C:18]4([CH3:28])[CH2:19][CH2:20][C:21](=O)[CH2:22]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1.C1COCC1>[CH:1](=[C:21]1[CH2:22][C:23]2[C:18]([CH3:28])([CH:17]3[CH:26]([CH2:25][CH:24]=2)[CH:13]2[CH2:12][CH2:11][CH:10]4[CH:9]([CH3:30])[N:8]([CH3:7])[CH2:29][C:14]24[CH2:15][CH2:16]3)[CH2:19][CH2:20]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC1C2CCC3C4CC=C5CC(=O)CCC5(C)C4CCC32CN1C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC=C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
Potassium t-butoxide (1.0 M in THF, 0.3 mL, 0.30 mmol) was added dropwise to a stirred solution of ethyl triphenylphosphonium bromide (156 mg, 0.42 mmol) in 2 mL anhydrous toluene. A bright orange suspension resulted and was stirred at room temperature for 5 hours. Compound 130B (25 mg, 0.076 mmol) in 1 mL THF was added to the above suspension and stirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane to give the crude product, which was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (12 mg, 46% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1)#[N:15]
Reactant: OCCOCCc1ccc(Br)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCOCCO)cc1
Temperature: 145 °C

Procedure:
To a solution of 2-[2-(4-bromophenyl)ethoxy]ethanol (10.8 g, 0.044 mol; see step (iii) above in DMF (100 mL), CuCN (7.8 g, 0.088 mol) was added and refluxed at 140 to 150° C. overnight. After removal of DMF by distillation, the reaction was quenched by the addition of water. Inorganic matter was removed by filtration and the aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water and brine before being concentrated. The crude product was purified by column chromatography (silica gel: 60-120 mesh, petroleum ether:ethyl acetate (75:25) eluent). This yielded 4.3 g (51%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][O:11][CH3:16])[CH3:12])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(CCO)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To the solution of 3-(4-bromophenyl)butan-1-ol (791 mg, 3.47 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (278 mg, 6.94 mmol), the mixture was stirred at room temperature for 30 minutes, then iodomethane (985 mg, 6.94 mmol) was added, the mixture was stirred for 5 hours, then quenched with water (1 mL) concentrated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 1-bromo-4-(4-methoxybutan-2-yl)benzene (541 mg, 64%).
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH:11]=[O:12])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[C:7]([C:13]([F:14])([F:16])[F:15])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 39.9 g (156.9 mmoles) of (1-tert-butyl-5chloro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 300 ml of methanol was cooled to 0° C. Thereto was gradually added 6.5 g (172.6 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 37.7 g (yield: 93.6%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 4-cyanophenylboronic acid to give the title compound as off-white solid in 87% yield. MS: 292.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]OS(C)(=O)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:31]>>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][NH2:31])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: N
Reactant: Cc1ccc2c(c1)c1c(n2CC(CCOS(C)(=O)=O)c2ccncc2)CCN(C)C1
Product: Cc1ccc2c(c1)c1c(n2CC(CCN)c2ccncc2)CCN(C)C1

Procedure:
Methanesulfonic acid 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl ester (200 mg, 0.468 mmol) in 10 mL of aqueous ammonia was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was dried and the crude product was purified by reverse phase chromatography to obtain 33 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butylamine as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.5 (d, 2H), 7.5 (m, 2H), 7.25 (d, 1H), 7.24 (s, 1H), 7.05 (t, 1H), 4.6 (d, 1H), 4.5 (d, 1H), 4.3 (m, 1H), 4.23 (t, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.08 (d, 3H), 2.8 (m, 2H), 2.7 (m, 2H), 2.4 (s, 3H), 2.25 (m, 1H), 2.2 (m, 1H). Separation by chiral HPLC provides enantiomers II-231a-b.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].N1CCCC1>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:35]3[CH2:36][CH2:37][CH2:34][CH2:33]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Solvent: CC#N
Solvent: C1CCNC1
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (3.334 g, 7.31 mmol) in anhydrous acetonitrile (4 mL) was added triethylamine (3.06 mL, 21.94 mmol) and pyrrolidine (1.831 mL, 21.94 mmol). The solution was stirred at 70° C. for 18 hours. A further equivalent of pyrrolidine (0.61 mL, 7.31 mmol) and triethylamine (1.019 mL, 7.31 mmol) were added to the reaction mixture. The solution was stirred at 70° C. for a further 3 hours. The cooled reaction mixture was evaporated in-vacuo and the residue partitioned between ethyl acetate and water/brine (1:1). The organic phase was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a sticky brown gum (4.226 g). The gum was dissolved in the minimum volume of dichloromethane, loaded onto a 340 g silica pre-conditioned cartridge and purified by chromatography using dichloromethane over 1 column volume followed by 0-30% methanol (+1% triethylamine) in dichloromethane gradient over 14 column volumes followed by 30% methanol (+1% triethylamine) in dichloromethane over 3 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a sticky brown gum (1.838 g).
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:17]([O:24][C:25](=[O:37])[NH:26][C:27]([C:33](=[NH:36])[NH:34][OH:35])([CH3:32])[CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25](=[O:37])[NH:26][C:27]([CH3:32])([C:33]1[N:36]=[C:1]([CH3:2])[O:35][N:34]=1)[CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)O
Reactant: CC(CC1CC1)(NC(=O)OCc1ccccc1)C(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(CC2CC2)NC(=O)OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
To a solution of acetic acid (139 mg, 132 μl, 2.31 mmol) in dry DMF (8 ml) under an argon atmosphere was added carbonyldiimidazole (374 mg, 2.31 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. Addition of a solution of [2-Cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamic acid benzyl ester (Example 66c, 0.64 g, 2.2 mmol) in dry DMF (4 ml) and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was then stirred at 130° C. under microwave radiation for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (542 mg, 78%) as a yellow oil. MS (ESI, m/z): 316.5 (M+H+).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[C:1]1([CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc2ccccc12)C=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
1-Naphthaldehyde (22, 1.36 ml, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.63 g (38%) of a yellow solid: mp 132-133° C. [expected mp 128° C.]; 1H NMR: δ 7.24 (d, 2H, J=15.7 Hz), 7.57 (m, 6H), 7.92 (m, 6H), 8.28 (d, 2H, J=8.0 Hz), 8.65 (d, 2H, J=15.5 Hz); 13C NMR: δ 123.4, 125.1, 125.4, 126.2, 126.9, 128.1, 128.7, 130.7, 131.7, 132.2, 133.7, 140.3, 188.5.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([OH:18])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([Cl:22])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sccc1NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
3-Benzenesulfonylaminothiophene-2-carboxylic acid (0.61 g, 2.15 mmol) was suspended in dichloromethane (8.6 mL). The resulting mixture was sequentially treated with N,N-dimethylformamide (1 drop), and, in two portions, oxalyl chloride (0.42 mL, 4.8 mmol). After stirring briefly at room temperature, the foaming subsided and the solution was refluxed until the reaction was complete. The mixture was concentrated to dryness, re-dissolved in dichloromethane, and filtered through very small pad of course silica gel, eluting with dichloromethane. Upon concentration of the eluent, the desired 3-benzenesulfonylaminothiophene-2-carboxylic acid chloride was obtained as a yellow solid (0.32 g, 49%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+].IC>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1C
Temperature: 60 °C
Yield: 103.3 %

Procedure:
A mixture of 3-bromo-2-methylbenzoic acid (16 g, 74.4 mmol), sodium bicarbonate (12.5 g, 148.8 mmol) and iodomethane (21.2 g, 148.8 mmol) in DMF (160 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into ice water (400 mL). The mixture was extracted with ethyl acetate (4×100 mL). The EtOAc solution was washed with water (3×10 mL), brine (100 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-methylbenzoate (17.6 g, 100%) as an oil: 1H NMR (CDCl3) δ 7.70 (t, J=7.6 Hz, 2H), 7.08 (t, J=7.9 Hz, 1H), 3.90 (s, 3H), 2.67 (s, 3H).