Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=1.C(=O)=O.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]=[O:36])=[C:33]([CH:41]([CH3:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:32]=1>C1COCC1>[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]([C:21]2[C:22]([O:24][CH3:25])=[N:23][C:18]([O:17][CH3:16])=[N:19][CH:20]=2)[OH:36])=[C:33]([CH:41]([CH3:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:32]=1
Reactant: COc1ccnc(OC)n1
Reactant: COc1cc(C=O)c(C(C)Cc2ccccc2)cc1OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncc(C(O)c2cc(OC)c(OC)cc2C(C)Cc2ccccc2)c(OC)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Freshly distilled 2,2,6,6-tetramethyl piperidine (0.85 mL, 5.0 mmol) was dissolved in 20 mL THF and cooled to 0° C. n-Butyllithium (2.0 mL, 2.5 M in hexanes) was added drop-wise over 5 minutes and the mixture was allowed to stir for 30 minutes and then cooled to −78° C. 2,4-Dimethoxypyrimidine (0.353 g, 2.52 mmol) was added drop-wise over 5 min. After 45 min the solution was transferred via a dry ice cooled cannula to a solution of 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzaldehyde (0.717 g, 2.52 mmol) in 20 mL THF at −78° C. After stirring for 1 hour the solution was warmed to room temperature and quenched by the slow addition of 50 mL 10% NH4Cl. After 100 mL of H2O was added the mixture was extracted with ethyl acetate, washed with H2O and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification via flash chromatography (3:2 hexane/ethyl acetate) afforded [4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-(2,4-dimethoxy-pyrimidin-5-yl)-methanol (0.551 g, 52%) as a clear oil.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:97]=[CH:96][C:49]([CH2:50][CH2:51][O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]([CH2:67][C@@H:68]([C:77]2[CH:86]=[CH:85][C:84]([O:87][C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])=[C:83]3[C:78]=2[CH:79]=[CH:80][C:81](=[O:95])[NH:82]3)[O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:48][CH:47]=1>>[C:91]([O:90][C:88]([O:87][C:84]1[CH:85]=[CH:86][C:77]([C@@H:68]([O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH2:67][N:59]([CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33](=[O:34])[NH2:35])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:14]=3)=[CH:97][CH:96]=2)[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[C:78]2[C:83]=1[NH:82][C:81](=[O:95])[CH:80]=[CH:79]2)=[O:89])([CH3:94])([CH3:93])[CH3:92]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OC(=O)OC(C)(C)C)c7[nH]c(=O)ccc67)C(=O)OC(C)(C)C)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 111 in place of 8-aminooctanol. ES/MS calcd. for C61H75N6O11SSi+ 1127.5. Found m/z=1127.7 (M+H)+.
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])#[N:14]>C1(C)C=CC=CC=1>[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)([CH3:21])[CH3:20])#[N:14]
Reactant: CC(C)(Br)C(=O)NCCC#N
Reactant: Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)NCCC#N

Procedure:
Into a 25 liter reactor fitted with cooling and stirring means there were poured 3 liters of ethanol, 60 g of sodium and 250 g of p-chlorophenol (1.944 mol). After stirring for 1 hour there were added 3 liters of toluene and the ethanol/toluene azeotrope was removed by distillation; 2 more liters of toluene were added and also 425 g of N-cyanoethyl α -bromo-isobutyramide, (1.944 mol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:11][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:23][CH2:22]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(Cc2cc3ccccc3n2C)CC1

Procedure:
1-Methyl-1H-indole-2-carbaldehyde and 1-(2-methoxyphenyl)piperazine were processed as described in Example 7 to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 3.0 (m, 2H), 3.45 (m, 2H), 3.74 (m, 4H), 3.86 (s, 3H), 3.88 (s, 2H), 4.70 (s, 3H), 6.83 (s, 1H), 6.90-7.14 (m, 5H), 7.28 (m, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz). MS (DCI/NH3) m/z 336.1 (M+H)+. Anal. Calcd for C21H25N3O: C, 75.19;H, 7.51; N, 12.53. Found: C, 74.45;H, 7.43; N, 12.37.
Reaction SMILES: [CH:1]1([O:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:56][C:49]1[N:50]=[C:51]([NH:12][O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NOC1CCCc2ccccc21
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NOC4CCCc5ccccc54)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 15 %

Procedure:
The title compound was prepared according to method B as described in examples 4 and 5 by reacting O-[1,2,3,4-tetrahydronaphth-1-yl)hydroxylamine (prepared by the procedure described in example 6) (0.35 g, 2.0 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 1.58 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-N-(1,2,3,4-tetrahydronaphth-1-yloxy)adenosine (0.10 g, 15%) (after column chromatography) as a colourless foam (a mixture of diastereoisomers), 1H NMR (DMSO-d6)γ 1.65 - 2.85 (6H, m,--CH2CH2CH2 --), 3.53-3.61 (1H, m, H-5'a), 3.64-3.70 (1H, m, H-5'b), 3.94 (1H, br d, H-4'), 4.16 (1H, br d, H-3'), 4.53 (1H, q, H-2'), 5.07 (2H, m, 5'-OH and OCH--), 5.26, 5.53 (2H, 2d, 2'- and 3'-OH), 5.88 (1H, d, H-1'), 7.13-7.30 (3H, m, Ar-H), 7.88-7.96 (1H, m, Ar-H), 8.52 (1H, s, H-8), 11.60 (1H, br s, N-H). HPLC retention time 20.71 and 20.95 min (gradient elution over 25 min.; 25-45% acetonitrile/0.1M.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][C:22](OC)=[O:23])[CH2:20][CH2:19]3)=[C:8]2[CH3:26])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][CH2:22][OH:23])[CH2:19][CH2:20]3)=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C1(CCO)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a -78° C. solution of ester from Step 7 (442 mg, 1 mmol) in 5 mL THF was added DIBAH (1.5M in toluene, 2 mL, 3 mmol), and the mixture was stirred for 2 hours with slow warming to 0° C. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was filtered through a plug of silica gel to give 319 mg of the title compound which was used without further purification.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][OH:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][OH:13])[C:9]=2[CH:14]=1
Reactant: COc1cc2c(cc1Br)C(CO)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Br)C(CO)CNCC2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 1 hour at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.006 g clear oil. 1H NMR (400 MHz, CD3OD) d 7.28 (s, 1 H), 6.79 (s, 1 H), 3.84 (m, 2 H), 3.0−2.8 (m, 7 H). MS calculated for C12H16BrNO2+H: 286, observed: 286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[C-:36]#[N:37].[Na+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([C:36]#[N:37])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 6.6 %

Procedure:
To a solution of the compound obtained in Example 33 (300 mg) in dimethylformamide (10 mL) was added sodium cyanide (42.1 mg) and the mixture was stirred at 10° C. for 1.5 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and an aqueous sodium hydrogencarbonate solution and the mixture was stirred. The organic layer was washed with water and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 65/35) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-cyano-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (17.8 mg; yield: 81%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:12](=[O:13])[O:8][C:6](=[O:7])[C:5]2=[CH:9][CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a mixture of 10.0 g (58.0 mmol) of 4-chloroanthranilic acid in 100 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 8.78 g (76.2%) of the 4-chloroisatoic anhydride as a light brown solid. MS (Cl mode) m/z 198 (M+H, 100%), Cl pattern 200, 35%.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([CH3:26])=[N:23][CH:22]=2)=[C:17]([O:27][CH3:28])[CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]>ClC1C=CC=CC=1>[CH3:28][O:27][C:17]1[CH:16]=[C:15]([C:14]2[N:3]=[N:2][N:1]3[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11][CH2:12][C:13]=23)[CH:20]=[CH:19][C:18]=1[C:21]1[O:25][C:24]([CH3:26])=[N:23][CH:22]=1
Reactant: CCOC(=O)C(CCCC#Cc1ccc(-c2cnc(C)o2)c(OC)c1)N=[N+]=[N-]
Solvent: Clc1ccccc1
Product: CCOC(=O)C1CCCc2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnn21
Temperature: 110 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 2-azido-7-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]hept-6-ynoate (1.40 g) in chlorobenzene (28 mL) was stirred at 110° C. for 4 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.34 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:20]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClC(Cl)C.C(OCC)(=O)C>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Br:20])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Br)c21
Temperature: 75 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
A solution of (S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.875 g, 3.0 mmol) in dichloroethane (7 mL) was treated with N-bromosuccinimide (0.284 g, 2.1 mmol) and trifluoromethansulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 75° C., diluted with ethyl acetate (20 mL) and extracted with water (2×10 mL). The organics were dried with MgSO4, filtered and concentrated. Flash chromatography (5% EtOAc in hexanes, silica) resulted in 0.13 g of a clear oil. MS calculated for C13H12BrClF3NO+H: 370, observed: 370.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Cl)c1
Yield: 86.8 %

Procedure:
(3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was dissolved in ethanol (37.7 mL) and treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a clear oil: EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0442.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.C(I)[I:22].CCOC(C)=O>C1COCC1.[Cu]I>[I:22][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1
Reactant: ICI
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Temperature: 70 °C

Procedure:
N-(2-Aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide [prepared according to Specific Method 1] (200 mg, 0.732 mmol), CuI (140 mg, 0.732 mmol) and CH2I2 (0.30 mL, 3.73 mmol) were taken up in THF (3.7 mL) in a 16×100 mm resealable pyrex tube. The tube was sealed and the mixture was heated at 70° C. for 2 h. After cooling to rt, the crude reaction mixture was taken up in 1:1 EtOAc:1N HCl and the layers were separated. The organics were washed with saturated NH4Cl then dried over Na2SO4. Purification by MPLC (Isco—100% EtOAc eluent) afforded N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([S:39]([N:38]([CH3:43])[CH3:37])(=[O:41])=[O:40])[CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (20 mg, 0.049 mmol) and triethylamine (0.014 mL, 0.097 mmol) in CH2Cl2 (0.7 mL) at 0° C. was added dimethylsulfamoyl chloride (17.4 mg, 0.122 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 3 h. The reaction mixture was quenched with sat. aq. NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 40% EtOAc) to afford 4-(2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)-N,N-dimethyl-5,6-dihydropyridine-1(2H)-sulfonamide (15 mg, 0.027 mmol, 57% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 2H), 7.64 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.7, 3.7 Hz, 1H), 4.17 (ddd, J=13.4, 7.2, 3.9 Hz, 2H), 3.98-3.92 (m, 2H), 3.70 (ddd, J=13.4, 8.3, 3.6 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.86 (s, 6H), 2.69-2.61 (m, 2H), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H). LCMS (m/z)=519 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:5][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][CH2:9][N:2]1[CH3:1]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C
Temperature: 25 °C

Procedure:
To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0° C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH ~12 with K2CO3 (solid) and extracted with CH2Cl2. The combined CH2Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>COCCOC.CO.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2ccccn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-bromopyridine (1.91 ml) and tetrakis(triphenylphosphine)palladium(0) (0.46 g) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium bicarbonate (20 ml) and a solution of dihydroxy(3-nitrophenyl)borane (3.67 g) in methanol (10 ml). The mixture was stirred at 80° C. for 2.5 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:1)) to give 2-(3-nitrophenyl)pyridine (1.35 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)cc1

Procedure:
The title compound, yellow solid, MS: m/e=306.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-methoxybenzene.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:8]1(=[O:9])[N:4]([CH2:3][CH:2]([OH:1])[CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[N+:16]([O-:18])=[O:17])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]

Procedure:
To a solution of N-(2,3-epoxypropyl)phthalimide (commercially available, 20.3 g, 0.1 mol) in ethanol (200 mL), 2-nitroimidazole (11.3 g, 0.1 mol) and potassium carbonate (1.2 g) were added and the reaction mixture was refluxed for 6 hrs. The reaction mixture was cooled and poured into water (700 ml) and the yellow solid formed was filtered and dried. Yield 28.2 g (89%). It was recrystallized from methanol. mp. 213°-214° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH:11]([CH3:26])[CH2:12][CH:13]1[CH2:15][N@@:14]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(O)C>[CH3:26][CH:11]([CH3:10])[CH2:12][CH:13]([NH:14][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:15][N:8]([CH2:15][CH:13]([NH:14][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:12][CH:11]([CH3:10])[CH3:26])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)CC1CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCO
Product: CC(C)CC(CN(CC(=O)OC(C)(C)C)CC(CC(C)C)NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A refluxing solution of 15.1 g (a 10% excess) of glycine t-butyl ester in 200 ml of absolute ethanol is treated dropwise over one hour with a solution of 24.2 g of (S)-2-(2-methylpropyl)-1-aziridinecarboxylic acid, phenylmethyl ester in 50 ml of absolute ethanol. The refluxing is continued over two nights. The solvent is removed under reduced pressure and the residue chromatographed on 1.5 kg of silica gel, eluting with chloroform/ethylacetate (3:1). Combining the fractions containing the faster eluting compound gives 14.3 g of an oil which crystallizes on standing. A small example, recrystallized from hexane has mp 107°-108°, [α]D23 -16.3° (c 1.03, methanol). Spectral and elemental analysis shows this to be [S-(R*,R*)]-N,N-bis[4-methyl-2-[[(phenylmethoxy)carbonyl]amino]pentyl]glycine, 1,1-dimethylethyl ester.