Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][Cl:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+]>CO>[Cl:14][CH2:13][CH2:12][O:11][C:9]1[CH:10]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: Cc1cc(OCCCl)ccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCl)cc1
Temperature: 50 °C
Yield: 93.2 %

Procedure:
To methyl 4-(2-Chloroethoxy)-benzoic acid (11.8 gm, 53.5 mmol) dissolved in 118 mL of methanol was added 2N KOH (35mL, 1.3 equiv.) and the resulting solution was heated at 50° C. for 24 hrs. The reaction was cooled to room temperature and the methanol evaporated off. The residue was diluted with water and extracted once with ethyl acetate. The aqueous layer was then acidified with 6N HCl and a precipitate formed which was filtered off, washed well with water, and pumped dry under vacuum to yield 10 gm of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.S(Cl)(Cl)=O.[O:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.N1C=CC=CC=1>ClCCl>[O:31]1[CH:35]=[CH:34][C:33]([NH:36][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:16][N:15]=[CH:14]4)[CH:4]=2)=[N:32]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 25 °C

Procedure:
A solution of 4-methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (Example 8, 160 mg, 0.45 mmol) in thionyl chloride (1.0 mL, 1.37 mmol) was stirred at RT for 1 h. Excess SOCl2 was removed under reduced pressure and the residue was treated with 1 mL of toluene and concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL), and isoxazol-3-amine (58 mg, 0.69 mmol) followed by pyridine (72 mg, 0.92 mmol) was added. After the resulting mixture was refluxed for 1 h, cooled to RT, diluted with dichloromethane, and washed with 1 N NaOH. The dichloromethane layer was dried, concentrated, and purified on an ISCO 12 g column (eluted with 5-15% MeOH in ethyl acetate) to provide N-(isoxazol-3-yl)-4-methyl-3-(1-morpholinophthalazin-6-yl)benzamide as an amorphous off-white solid. Found MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[OH:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCOCC.CCCCCC>[ClH:34].[Cl:34][C:31]1[CH:32]=[CH:33][C:28]2[N:27]=[C:5]([CH2:4][CH:3]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH:11]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=4)[CH2:10]3)[C:2]([F:26])([F:25])[F:1])[O:35][C:29]=2[CH:30]=1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)c1cccc(C2CCCN(CC(Cc3nc4ccc(Cl)cc4o3)C(F)(F)F)C2)c1
Temperature: 135 °C
Yield: 48.4 %

Procedure:
In a 5 mL microwave vial, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (50 mg, 130 μmol), 2-amino-5-chlorophenol (28.1 mg, 196 μmol) and p-toluenesulfonic acid (4.96 mg, 26.1 μmol) were combined in toluene (1.00 ml) to give a dark brown suspension. The tube was sealed and heated in a microwave at 135° C. for 2 h, diluted with ethyl acetate (30 ml), washed with a saturated solution of Na2CO3 (30 ml) and H2O (30 ml), dried over MgSO4, filtered and concentrated in vacuo to give an oil. The oil was purified on a silica column (100% CH2Cl2 to 50% ethyl acetate/CH2Cl2 gradient) to afford an oil which was dissolved in ether/hexane (1 ml/1 ml), treated with a 4N HCl solution in dioxanes (0.02 ml) and concentrated to afford 25 mg (37%) of 6-chloro-2-{3,3,3-trifluoro-2-[3-(3-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-propyl}-benzooxazole hydrochloride as a light red solid. MH+=491.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (402 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 53%). MS (ISN) 582.0 [(M−H)−]; mp 226-227° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (350 mg, 1.003 mmol) and 2-methylbenzenesulfonyl chloride (0.145 mL, 1.00 mmol) the title compound of Step A was obtained as a yellow solid (140 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 8.35-8.65 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.11-7.50 (m, 6H), 6.73 (d, J=5.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.54 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]#[N:15])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:41][O:42][P:43](=[O:54])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>CC(C)=O>[C:14]([C:9]1[N:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[C:3]2[N:4]([CH2:41][O:42][P:43](=[O:54])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[O:44][C:45]([CH3:48])([CH3:46])[CH3:47])[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:6][C:7]=2[N:8]=1)#[N:15]
Reactant: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)n(COP(=O)(OC(C)(C)C)OC(C)(C)C)c2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (0.5 g, 0.0012 mol), K2CO3 (0.485 g, 0.0036 mol) and acetone (10 ml) were taken and stirred for 20 minutes at room temperature. NaI (0.702 g, 0.0047 mol) was added and then Phosphoric acid di-tert-butyl ester chloromethyl ester (0.619 g, 0.0024 mol in 2 ml acetone) was added to the reaction mixture drop wise. The reaction mixture was heated at 45° C. for 16 h. The reaction mixture was filtered through celite and washed with acetone. The organic layer was concentrated and the residue was taken in ethyl acetate (30 ml) and saturated NaHCO3 solution (20 ml). The organic layer was separated and washed with saturated sodium thiosulphate solution (20 ml). The organic layer was washed with 0.5 N HCl solution (20 ml) and brine solution (20 ml). The organic layer was dried over sodium sulphate and evaporated to obtain brown colored mass. The crude product, which is a mixture of N7 and N9 isomers was purified by column chromatography (230-400 mesh silica gel and it was first treated with 5% triethyl amine in hexane) using 5-20% acetone in hexane (with 0.5 to 1% triethyl amine) as an eluent to obtain N7 isomer (0.34 g, 45%) and N9 isomer (0.11 g, 14%)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[C:19](O)=[O:20]>>[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[C:19]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1cc(-c2ccccc2)ccc1C(=O)O
Product: Cc1cc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (31, 0.22 mmol) and 3-methyl-1,1′-biphenyl-4-carboxylic acid (D58) (55 mg, 0.26 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91(dd, 1H), 8.14 (m, 3H), 7.86 (d, 1H), 7.78 (br, 1H), 7.66 (d, 1H), 7.62 (d, 2H), 7.53 (m, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.36 (dd, 1H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Oc1ccc(CCBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(O)cc3)C2=O)cn1
Yield: 31 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-hydroxyphenethyl bromide. Yield: 31%. MS M+H calculated 396.16. found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.41 μM.
Reaction SMILES: [O:1]1[CH:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:2]1([CH3:24])[C:3]([F:6])([F:5])[F:4].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)C>[F:6][C:3]([F:4])([F:5])[C@:2]([OH:1])([CH3:24])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC1(C(F)(F)F)OC1Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@](O)(/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 71.4 %

Procedure:
2,3-Epoxy-1,1,1-trifluoro-2-methyl-4-(4-phenylsulfonylphenyl)butane (1.68 g) was dissolved in 250 mL ethanol and 150 mL 6N NaOH was added. The mixture was stirred for 2 hours, and 500 mL of saturated aqueous. NaHCO3 was added. The mixture was extracted with ether and the organic layers were combined, dried, and evaporated to yield the title compound as a white solid (1.2 g, 70%); [α]23 =-28.35 (c=1.05, MeOH); NMR (CDCl3): 7.93-7.85 (m,4, Ar), 7.58-7.45 (m,5, Ar), 6.90-6.84 (d,1, vinylic), 6.40-6.34 (d,1, vinylic), 2.75 (s,1, OH), 1.55 (s,3, CH3); MS: m/z=357(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH3:16])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH3:16])[CH2:9][C:10](=[O:11])[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a −78° C. solution of (S)-3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-(R)-(2-methyl-propane-2-sulfinylamino)-butyramide (1.5 g, 3.7 mmoles; 1.0 equiv) in THF (53 mL) is added methylmagnesium bromide (6.2 mL, 18.5 mmoles, 5.0 equiv) and the reaction is allowed to warmed to ambient temperature. After 1 h, the reaction is cooled to −78° C. and quenched with saturated aqueous ammonium chloride. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (>95% yield): MS (m/z) 360, 362 (M+1)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Cl:14][C:15]1[C:16]([CH3:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O.O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([CH3:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:5]=[C:4]([CH3:3])[C:12]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 58.6 %

Procedure:
At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to a suspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 25 minutes during which time the suspension became a nearly clear solution. To the resultant mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.35 g, 3.61 mmol, from Example 1, step 5) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 1.03 g (59%) of the desired product as a yellow gum. The racemic products were applied on a Phenomenex Lux-Cellulose 2 column (21.1×250 mm, 5 micron particle size), eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 4 mg/injection, to provide two enantiomers. The retention time of the first peak was 8.34 min and the retention time for the second peak was 10.92 min. Peak 1 (463 mg), LCMS calculated for C24H32ClN6O3 (M+H)+: m/z=487.2; Found: 487.1. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.37 (s, 1H), 6.30, (q, 1H), 5.40 (s, 2H), 4.23 (m, 2H), 4.17-4.00 (m, 3H), 3.57 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.76 (d, 3H), 1.37 (s, 9H) ppm.
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].N1CCCN2CCCCCC=12.[N+:18]([CH:21]([CH3:23])[CH3:22])([O-:20])=[O:19]>>[CH3:22][C:21]([N+:18]([O-:20])=[O:19])([CH3:23])[CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CCS(C)(=O)=O)[N+](=O)[O-]
Yield: 72.8 %

Procedure:
A solution of (methylsulfonyl)ethene (1.51 mL, 17.24 mmol, Sigma-Aldrich) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.86 ml, 25.9 mmol) in 2-nitropropane (72.8 mL, 810 mmol, Sigma-Aldrich) was stirred at RT for 2 d. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM followed by 1% 2 M NH3 in MeOH/DCM to give 3-methyl-1-(methylsulfonyl)-3-nitrobutane (338a, 2.45 g, 12.55 mmol, 73% yield) as a white solid. 1H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 1.31 (s, 6H) 2.08 (d, J=17.02 Hz, 1H) 2.08 (dd, J=4.30, 3.52 Hz, 1H) 3.05 (s, 3H) 3.33 (d, J=17.02 Hz, 1H) 3.33 (t, J=3.91 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:22](=[NH:23])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-trifluoromethylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80–85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[Li][Li].C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane was dissolved in 100 ml of ether. The solution thus obtained was taken to −20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-bis(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of −40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3(OCCO3)[CH2:13][CH2:12]2)[CH:3]=1.[O:21]1C2(CCCC(C3C=C(O)N4N=CC=C4N=3)C2)[O:24][CH2:23][CH2:22]1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)CC2)OCC1>>[Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:12][CH2:13][CH2:14][C:19]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:20]2)[CH:3]=1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: Oc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12
Agent: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Clc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12

Procedure:
7-Chloro-5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidine is synthesized in a manner similar to the synthesis of 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine, but with 5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=1)[C:5]2=[O:36]>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:35][O:34][CH2:33][N:32]1[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:6]3[C:5](=[O:36])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:5](=[O:36])[NH:6][CH2:7][CH2:12][CH3:13])[CH:3]=4)[N:8]=[C:7]3[CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[N:29][N:30]=[N:31]1
Reactant: CCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCNC(=O)Oc1ccc2nc(CCC)n(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Yield: 158.7 %

Procedure:
A mixture of 6-hydroxy-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.15 g) propyl isocyanate (0.9 ml) in a mixture of THF (5 ml) and pyridine (2 ml) was heated under reflux for 6 days. The reaction mixture was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid and water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale yellow powder (0.14 g, 79%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH2:12][CH2:11]1
Reactant: NCC1CCC(CN)CC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylsulfamoyl chloride (one mol-equivalent, ClSO2N(CH3)2) was added to a stirred solution of 1,4-bis-aminomethylcyclohexane (3 mol-equivalents) and diisopropylethylamine (1 mol-equivalent) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure and chromatographed (silica) to give the desired product as viscous oils. (Scheme 1A)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:16][CH2:15]3)=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.CCN(CC)CC.Cl[C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]3([CH3:17])[CH2:15][CH2:16]3)=[O:12])=[CH:9][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(NC(=O)c2c[nH]c3ncc(Br)nc23)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(NC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Br)nc23)CC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-N-(1-methylcyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (600 mg, 2.1 mmol) in 20 mL of dry THF was added Et3N (0.42 mL, 4.2 mmol) and reaction mixture stirred for 5 mins, then (chloromethanetriyl)tribenzene (540 mg, 2.53 mmol) was added and reaction mixture stirred for 10 mins. Then, the reaction was heated to 60° C. and stirring continued for 3 hrs. The reaction was quenched with brine (10 mL), product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give 2-bromo-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (400 mg, 37%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 8.01 (s, 1H), 7.31-7.26 (m, 15H), 1.51 (s, 3H), 1.25 (s, 2H), 0.90-0.74 (m, 2H). LCMS: (M+H)+=537/539.