Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes). The fractions containing the desired product were allowed to stand for 3d. Some fractions had crashed large crystals (collected 240 mg, pure desired product by 1H NMR). All fractions containing the desired product were collected and concentrated to a yellow solidified foam which was slurried with Et2O (˜40 mL). The white solid that formed was collected by filtration and rinsed with Et2O to yield (1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retention time 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m, 1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44 (m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53 (m, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([C@H:11]1[NH:14][C:13](=[O:15])[CH2:12]1)#[CH:10]>ClCCl.C(N(C(C)C)C(C)C)C>[Si:1]([N:14]1[C@H:11]([C:9]#[CH:10])[CH2:12][C:13]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[C@@H]1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
tert-butyldimethylsilyl chloride (1.42 g) was added to a mixture of 4(S)-ethynyl-2-azetidinone (0.78 g) in dichloromethane (10 ml) and ethyldiisopropylamine (2.14 ml) at room temperature. The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane-ethyl acetate (9:1) to give 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (1.4 g) as a colorless oil.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=2)[CH:18]=[N:17]1>CN(C)C=O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:23]=2)[CH:18]=[N:17]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc2cn[nH]c2c1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 1H-indazol-6-ylamine (66.6 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 79.4 mg (52%) of yellow solid mp >300° C.; MS (ESI) m/z 305.10 (M+1);
Reaction SMILES: C(O[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[OH-].[K+].C1CCCCC1.ClCCl.C(=O)=[O:25]>O>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([OH:25])=[CH:9][CH:8]=1)=[CH2:5]
Reactant: CC(=O)OC=Cc1ccccc1
Reactant: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCCCC1
Product: C=Cc1ccc(O)cc1

Procedure:
The reaction is based on that described by Corson et al. J Org Chem (1958) 544–549; molar ratios acetoxystyrene:base 1:1.5. The base, KOH in water (30%) was immersed in an ice bath and the acetoxystyrene was added dropwise over 30 mins (all reaction carried under N2; the reaction was TLC monitored (20–80 cyclohexane-dichloromethane) until all acetoxystyrene disappeared, then the pH was brought down to 8 with CO2; the resulting precipitate was filtered and washed with water, then recrystallised from boiling hexane and NMR characterised.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:13]=1[C:14]#[N:15].C1(C)C=CC=CC=1>CN1CCCC1=O.O>[C:14]([C:13]1[C:16]([C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=[CH:19][C:12]=1[O:2][C:1]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)#[N:15]
Reactant: Oc1cccc(O)c1
Reactant: N#Cc1c(Cl)cccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: N#Cc1c(Oc2cccc(O)c2)cccc1C(F)(F)F
Temperature: 62.5 °C
Reaction time: 2.5 h

Procedure:
Resorcinol [44.0 g (0.4 mol)] is partly dissolved in 170 ml of N-methylpyrrolidone, and potassium hydroxide [min. 85% pure; 34.5 g (0.52 mol)] and then 2-chloro-6-(trifluoromethyl)benzonitrile [20.5 g (0.1 mol)] are added. The mixture is stirred at 60-65° C. for 2.5 h. After addition of 300 ml of toluene and 400 ml of water, the aqueous phase is separated off and extracted once more with 300 ml of toluene. The combined organic phases are dried over MgSO4 and, after filtration, concentrated. Digestion of the oily residue with 150 ml of water, filtration and drying affords pale brownish crystals.
Reaction SMILES: C(N1C2=NC=[C:15](C(OCC)=O)[C:16]([NH:17]N)=[C:11]2[CH:10]=N1)C1C=CC=CC=1.C(N1C2=NC=C(C(OCC)=O)C(NN)=C2C=N1)C.C(N1C2N=CC3C(=O)NC4N(N=C(SC)N=4)C=3C=2C=N1)C.ClC1C2C=NC3N(CC)N=CC=3C=2N2N=CN=C2N=1.[CH2:82]([N:89]1[C:93]2[N:94]=[CH:95][C:96]3[C:97](=O)[NH:98][C:99]4[N:100]([N:102]=[CH:103][N:104]=4)[C:101]=3[C:92]=2[CH:91]=[N:90]1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1.C(N1C2N=CC3C(Cl)=NC4N(N=CN=4)C=3C=2C=N1)C1C=CC=CC=1>>[CH2:82]([N:89]1[C:93]2[N:94]=[CH:95][C:96]3[C:97]([NH:17][CH:16]([CH3:15])[CH2:11][CH3:10])=[N:98][C:99]4[N:100]([N:102]=[CH:103][N:104]=4)[C:101]=3[C:92]=2[CH:91]=[N:90]1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1c2cnn1Cc1ccccc1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccccc2)c1NN
Agent: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3nc(SC)nn3c12
Agent: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Product: CCC(C)Nc1nc2ncnn2c2c1cnc1c2cnn1Cc1ccccc1

Procedure:
By substituting 1-benzyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 1 (a), (b) then proceeding as in Example 2, 8-benzyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one and 8-benzyl-5-chloro-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and 8-benzyl-N-(1-methylpropyl)-8H-pyrazolo[4',3':5,6]pyrido[3,4e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine, respectively, are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH2:25][CH2:26][O:27][CH3:28])[C:17]=2[N:29]=1)[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH2:25][CH2:26][O:27][CH3:28])[C:17]=2[N:29]=1)[C:6]([NH:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1)=[O:8]
Reactant: COCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
A mixture of 0.11 g (0.00027 mole) of 3-methoxy-4-[9-(2-methoxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-40a), 0.115 g (0.0003 mole) of 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.166 mL (0.00096 mole) of ethyldiisopropyl amine and 2.0 mL of dimethylformamide was stirred for 5 minutes and then 0.047 g (0.00041 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.098 g of 3-methoxy-4-[9-(2-methoxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(1-methyl-piperidin-4-yl)-benzamide (I-40) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][Cl:14]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][Cl:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(OCCCl)c1
Reaction time: 18 h

Procedure:
To an argon-degassed solution of 1-chloro-2-(2-chloro-ethoxy)-4-nitro-benzene (2.9 g, <12.5 mmol due to contamination) in EtOAc (50 mL) was added 10% by weight Pd/C (1 g). The reaction was stirred under H2 for 18 h then filtered through Celite® and concentrated in vacuo to yield the title compound contaminated by the bromo adduct. MS (MH+)=206.1; Calc'd 206.07 for C8H9Cl2NO.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:47])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:47])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (224 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (320 mg, 75%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:20]([NH:27][C:28]([C:30]1[S:31][C:32]([N:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][C:37]2=[O:43])=[CH:33][C:34]=1[CH3:35])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([C:30]1[S:31][C:32]([N:36]2[CH:41]=[CH:40][C:39]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:38][C:37]2=[O:43])=[CH:33][C:34]=1[CH3:35])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use phenethyl 4-methylbenzenesulfonate in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 59% yield: mp 159-160° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.9 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.35-7.20 (m, 11H), 6.18 (dd, J=7.9, 2.6 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 4.27 (t, J=6.7 Hz, 2H), 3.04 (t, J=6.6 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.3, 162.4, 161.0, 139.6, 138.8, 137.7, 137.1, 135.0, 128.8, 128.3, 128.2, 127.3, 127.1, 126.6, 126.3, 120.5, 102.4, 96.8, 68.8, 42.5, 34.2, 15.5; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[Br:8][C:9]1[C:10](=[O:25])[CH2:11][CH2:12][C:13]2([CH3:24])[C:21]=1[C:20]1[C:15](=[CH:16][C:17]([O:22]C)=[CH:18][CH:19]=1)[CH2:14]2>>[Br:8][C:9]1[C:10](=[O:25])[CH2:11][CH2:12][C:13]2([CH3:24])[C:21]=1[C:20]1[C:15](=[CH:16][C:17]([OH:22])=[CH:18][CH:19]=1)[CH2:14]2
Reactant: COc1ccc2c(c1)CC1(C)CCC(=O)C(Br)=C21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC12CCC(=O)C(Br)=C1c1ccc(O)cc1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1M BBr3 in CH2Cl2 (0.200 mL, 0.2 mmol) was added to an ice-cold solution of 4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (10 mg, 0.033 mmol) in CH2CL2 (0.5 mL). The cooling bath was removed and the solution was stirred at room temperature for 30 minutes, then treated with more BBr3 in CH2CL2 (0.5 mL, 0.5 mmol) and stirred at room temperature for an additional 60 minutes. The solution was diluted with EtOAc (10 mL), washed with water (10 mL), 1N HCl (2 mL), and brine (10 ml), dried over MgSO4, filtered, and evaporated under vacuum to an oil. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 5% CH3OH in CH2Cl2, to afford 4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH:16](O)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(S(F)(F)[F:33])CC>>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH:16]([F:33])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCC(O)Cc1cccc(OCC2CCCCC2)c1
Reactant: CCN(CC)S(F)(F)F
Product: CC(C)(C)OC(=O)NCC(F)Cc1cccc(OCC2CCCCC2)c1

Procedure:
tert-Butyl 3-(3-(cyclohexylmethoxy)phenyl)-2-hydroxypropylcarbamate and DAST are reacted together to give tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)-2-fluoropropylcarbamate.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH2:19]Br)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:21]#[N:22].[Na+].[OH-].[NH4+]>CN(C=O)C.O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH2:19][C:21]#[N:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 79.3 %

Procedure:
1-Benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (200 mg, 0.6 mmol) and sodium cyanide (30 mg, 0.6 mmol) were stirred in DMF (6 mL). After several h, more sodium cyanide (60 mg, 1.2 mmol) was added to the reaction. A 25% ammonium hydroxide solution in water was added to the reaction and the reaction mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)acetonitrile (130 mg, yield 80%) MS (ESI) m/z: Calculated for C18H15N3: 273.13. found: 274.1 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:7][CH2:6][CH:5]1O)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:32])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:5]([F:32])[CH2:6][CH2:7][N:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1ncc([N+](=O)[O-])c1N1CCC(F)C(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-azido-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (1.25 g, 4.2 mmol) in dry DCM (20 ml) was added dropwise deoxo-Fluor® (3.8 mL, 10.6 mmol, 50% in THF) and the mixture was stirred at room temperature for 16 hr. The mixture was cooled in an ice bath, saturated aqueous NaHCO3 solution (40 mL) was added slowly (effervescence observed) and the mixture was extracted with DCM (2×20 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (2×10 mL), passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give 4-azido-5-fluoro-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow gum (0.91 g). A solution of this gum (0.9 g, 3.0 mmol) in THF/water (20 mL/4 mL) was treated with triphenylphosphine (0.8 g, 3.0 mmol) and the mixture was heated at 60° C. for 16 hr. The mixture was cooled and concentrated to 4 mL under reduced pressure, diluted with EtOAc (30 mL) and extracted with 1M HCl (4×10 mL). The combined aqueous extracts were washed with EtOAc (20 mL) and then basified with 6N NaOH and extracted with DCM (3×20 mL) The combined organic layers were separated, dried over MgSO4 and concentrated under reduced pressure to give 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.82 g). To a solution of this oil (0.8 g, 2.9 mmol) and DIPEA (0.77 mL, 4.4 mmol) in DCM (25 mL) was added di-tert-butyl-dicarbonate (0.97 g, 4.4 mmol) and the mixture stirred at room temperature for 16 hr. Water (15 mL) was added and the organic phase separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)-5-fluoroazepan-4-ylcarbamate as a yellow solid (1.1 g, 70% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.96 (s, 1H), 4.74 (td, J=7.4, 3.6 Hz, 1H), 4.65-4.58 (m, 1H), 4.16-4.05 (m, 3H), 3.42-3.29 (m, 2H), 3.16 (d, J=11.4 Hz, 2H), 2.31-2.18 (m, 2H), 2.20-2.06 (m, 2H), 1.94-1.82 (m, 1H), 1.60-1.45 (m, 10H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:35][C:36]1[C:37]([C:38]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[N:13]=[CH:14][N:15]=3)[CH2:23][CH2:24]2)=[O:39])=[CH:41][CH:42]=[CH:43][N:44]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4Cl)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A25 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), 2-chloro-nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.91 (m,1H), 2.00 (m, 1H), 2.14 (m, 2H), 3.08 (s, 3H), 3.36 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 5.72 (m, 1H), 7.36 (m,1H), 7.69 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (m, 1H), 8.47 (m, 1H), 10.20 (s, 1H). Exact mass calculated for C22H21ClN6O6S 532.09, found 533.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:6]=[CH:5][N:4]=1.[H-].[Na+].[Cl:21][C:22]1[C:27]([N:28]=[C:29]=[O:30])=[C:26]([Cl:31])[C:25]([O:32][CH3:33])=[CH:24][C:23]=1[O:34][CH3:35].O>C1COCC1.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:34][CH3:35])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([Cl:31])[C:27]=1[NH:28][C:29](=[O:30])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Nc2ccccc2[N+](=O)[O-])ncn1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of N-methyl-N′-(2-nitro-phenyl)-pyrimidine-4,6-diamine (150 g, 0.61 mmol) in THF (15 mL) was added NaH (60%, 60 g, 1.5 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (180 g, 0.73 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours. Water (2 mL) was added to quench the reaction. The mixture was concentrated, and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=6:1-1:1 to obtain the title compound (54 mg, yield: 18%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.38 (s, 3H), 3.93 (s, 6H), 6.75 (s, 1H), 6.91 (s, 1H), 7.34 (t, 1H), 7.72 (t, 1H), 7.79 (d, 1H), 8.01 (d, 1H), 8.38 (s, 1H), 9.99 (s, 1H), 11.78 (s, 1H); MS (ESI): 493 [M+H]+.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[N:16]12[CH2:24][CH:20]([C:21](=O)[CH2:22]1)[CH2:19][CH2:18][CH2:17]2.O>CCCCCC.O1CCCC1>[S:9]1[CH2:10][CH2:11][CH2:12][S:13][C:8]1=[C:21]1[CH2:22][N:16]2[CH2:24][CH:20]1[CH2:19][CH2:18][CH2:17]2
Reactant: O=C1CN2CCCC1C2
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C1CSC(=C2CN3CCCC2C3)SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
n-Butyl lithium (6.05 ml of a 1.6M solution in hexane, 9.7 mmol) was added dropwise to a solution of 2-trimethylsilyl-1,3-dithiane (1.86 g, 9.7 mmol) in tetrahydrofuran (30 ml) at -30° C. and the reaction mixture stirred for 2 hours. A solution of 1-azabicyclo[3.2.1]octan-6-one (1.1 g, 8.8 mmol) in tetrahydrofuran (10 ml) was added dropwise and the reaction mixture allowed to warm to room temperature. Water (20 ml) was added and extracted (3×) with dichloromethane. The combined extracts were dried (MgSO4) and concentrated and the residue purified by chromatography on alumina eluting with dichloromethane/methanol (97:3) to give the title compound as a colourless oil (2 g); m/e 227 (M+); δ (360 MHz, CDCl3) 1.23-1.38 and 1.56-1.86 (1H and 3H respectively, each m, 3CH2 and 4CH2 ), 2.08-2.24 (2H, m, SCH2CH2), 2.76-3.00 (9H, m, 2×SCH2, 2CH2, 5CH and 8CH2), 3.42 (1H, d, J=17 Hz, one of 7CH2) and 3.56 (1H, d, J=17 Hz, one of 7CH2).