Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CO[C@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.11 g racemic 4-[2-((trans)-3-Methoxycyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol) using TBTU instead of HATU in DMF as solvent.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>O1CCCC1.CO>[CH:23]1([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:11]([C:8]3[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=3)=[CH:12]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a cooled solution (ice/methanol bath) of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (4.0 g, 10 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) was added sodium borohydride portion-wise. The reaction was stirred for a further 20 minutes and then quenched with 1M hydrochloric acid (20 ml). The methanol and tetrahydrofuran were removed in vacuo and dichloromethane (200 ml) and 2M hydrochloric acid (50 ml) were added. The organics were separated and washed with brine (50 ml), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography eluting with 50% (v/v) diethyl ether in heptane to give [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (3.15 g, 8.8 mmol) as a light pink solid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[NH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[NH2:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:25]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ncn3)cc(C)c21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To the mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.04 g, 4 mmol) and 4-amino-6-chloropyrimidine (520 mg, 4 mmol) in CH3CN (20 ml), added Cs2CO3 (3.9 g, 12 mmol). The mixture was stirred at 50° C. for 24 hours. The result mixture was diluted with EtOAc (200 ml), washed with water and brine, dried over Na2SO4. Concentrated to give light yellow oil used for next step without further purification. MS (ESI negative): (M−H)−=342.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[N:10]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)cc1Cl
Yield: 68412.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using 3-chloro-4-methylaniline (6.0 g, 0.0420 mmol), NaNO2 (8.56 g, 0.050 mmol), SnCl2.2H2O (23.7 g, 0.105 mmol) and conc. HCl (100 mL) to afford 4.5 g of the desired product.
Reaction SMILES: [CH2:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH:2]([CH3:4])[CH3:3].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][C:5]1([CH2:1][CH:2]([CH3:4])[CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: ClCCCCBr
Reactant: CC(C)CC1C(=O)Nc2ccccc21
Product: CC(C)CC1(CCCCCl)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-isobutyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chlorobutane.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]#[N:12].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]#[N:12]
Reactant: COc1ccc(F)c(C#N)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 55 %

Procedure:
Synthesised from commercially available 2,6-difluoro-3-methoxybenzenecarbonitrile. Boron tribromide solution (1.0 M in CH2Cl2, 118.3 ml, 118.3 mmol, 2 equiv.) was added slowly, dropwise to stirred solution of 2,6-difluoro-3-methoxybenzenecarbonitrile (10 g, 59.1 mmol, 1 equiv.) in CH2Cl2 (270 ml), at room temperature The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water (600 ml), separated and extracted with CH2Cl2 (200 ml×2). The extracts were washed with water (250 ml×3) and dried (Na2SO4) to give a buff solid (7.15 g). This was dissolved in dichloromethane (250 ml) and extracted with dilute aqueous NaOH (6 g in 250 ml of water×2). The basic extracts were washed with CH2Cl2 (100 ml×3) and then acidified to pH 2 using concentrated HCl, extracted with CH2Cl2 (150 ml×4), washed with water (100 ml×2) and dried (Na2SO4) to give the desired compound as a cream solid (5.05 g). Yield 55%, mp 119-121° C., HPLC (Gemini C18, 50×4.6 mm): m/z 154 [M−H]−, Rt=3.07 min.
Reaction SMILES: O[CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.[Cl:12][C:13]([Cl:28])([Cl:27])[CH2:14][O:15][C:16](=[O:26])[NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]1([CH2:19][O:18][N:17]([CH2:2][C@@H:3]2[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]2)[C:16]([O:15][CH2:14][C:13]([Cl:12])([Cl:27])[Cl:28])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 200.3 %

Procedure:
To a 0° C. solution, under argon, of 1.0 g of product from Example 6, 1.69 g of product from Example 70, 1.49 g of triphenylphosphine and 5.4 ml of tetrahydrofuran is added 0.988 g of diethyl azodicarboxylate in 1.4 ml of tetrahydrofuran. The reaction is stirred at room temperature for 48 hours, filtered and the filtrate concentrated in vacuo to give 5.18 g of thick oil. The oil is purified by chromatography (Silica Gel: 15-25% ethyl acetate/hexane) to give 0.805 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7]([N:12]=[C:13]=[O:14])(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(Cl)(Cl)Cl.ClCCCl>[C:7]([NH:12][C:13](=[O:14])[O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CN(C)CCO
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)OCCN(C)C
Yield: 99.9 %

Procedure:
Dimethylaminoethanol (0.89 g; 10 mmol) was dissolved in dry chloroform (20 ml) under ice-cooling, and a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added thereto under nitrogen stream. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give dimethylaminoethyl N-methacryloylcarbamate (2.00 g), which was recrystallized from a mixture of benzene and hexane to give colorless needle-like crystals. M.P., 71°-73° C.
Reaction SMILES: C(C1C=CC(C2ON=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=4)=CC=1C(F)(F)F)C(C)C.[CH3:30][N:31]1[C:39]([C:40]2[C:44]([C:45]([F:48])([F:47])[F:46])=[C:43]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:42][N:41]=2)=C2C(C3C=CC(C=C)=CC=3CC2)=[N:32]1>>[CH3:30][N:31]1[C:39]([C:40]2[C:44]([C:45]([F:47])([F:46])[F:48])=[C:43]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:42][N:41]=2)=[C:12]2[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:24]=[O:25])=[CH:20][C:21]=3[CH2:22][CH2:23]2)=[N:32]1
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1c-2nn(C)c1-c1noc(-c2ccccc2)c1C(F)(F)F
Product: Cn1nc2c(c1-c1noc(-c3ccccc3)c1C(F)(F)F)CCc1cc(C=O)ccc1-2

Procedure:
This compound was prepared according to the general procedure described for Preparation 23D, employing 240 mgs of 3-(2-methyl-7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)-5-phenyl-4-(trifluoromethyl)isoxazole (79B). Yield: 235 mgs (97%); LC/MS M+1=424.2.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19](I)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>>[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([C:38]4[O:39][C:35]([CH:31]5[O:32][CH2:33][CH2:34][O:30]5)=[CH:36][CH:37]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(I)cc12
Agent: Cl
Product: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(-c3ccc(C4OCCO4)o3)cc12

Procedure:
Prepared according to Procedure B from (4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ1H NMR (400 MHz, DMSO-d6) 10.49(s, 1H), 8.88(d, 1H), 8.63(s, 1H), 8.1(d, 2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m, 1H), 6.75(d, 1H), 6.01(s, 1H), 4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13][CH:12]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O=C1NC2C=CC=CC=2NCC1NC(OC(C)(C)C)=O>>[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:15]=2[N:14]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH:12]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccc1

Procedure:
Step 1 of Example 1 was repeated except that benzoyl chloride was used instead of pivaloyl chloride and that 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 4 was used instead of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:25](/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)\[C:26]([OH:28])=[O:27])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCc1ncc(/C=C(\C(=O)O)c2cccs2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (2 mmol), 2-thienylacetic acid (2.3 mmol), potassium carbonate (0.91 mmol), and acetic anhydride (1 mL) is heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction is diluted with water and the solid is separated, triturated several times with ether, and the solid is crystallized to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:17])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][F:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cc(F)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-5-fluorophenyl)methanol (4 g, 19.51 mmol) in DCM (39.0 mL) at 0° C., DAST (3.35 mL, 25.4 mmol) was added. The reaction mixture was allowed to return to room temperature and stirred at room temperature overnight. Sat. NaHCO3 was added, the reaction mixture was then extracted by DCM. The organic was dried and concentrated. The crude material was purified by flash chromatography (0-10% EtOAc/heptanes) to yield the final product as colorless oil. LCMS (m/z): no mass (MH+), 0.86 min. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 5.29 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10].CI.[C:27](OCC)(=O)C>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][N:8]([CH3:27])[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10]
Reactant: COc1ccccc1CNC(=O)c1ccc2cccnc2n1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1CN(C)C(=O)c1ccc2cccnc2n1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (10 mg) in DMF (1 mL) at 0° C. was added a solution of the compound of Example 1 (68 mg, 0.23 mmol) in DMF (1mL). The reaction mixture was stirred at the same temperature for 30 minutes then methyl iodide (20 μL, 0.32 mmol) was added. Reaction mixture was stirred at room temperature overnight. It was then poured into ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give a white solid. Purification was done using a silica gel column and ethyl acetate as the eluent. 1H NMR (300 MHz; CDCl3): Mixture of rotamers 9.13 (m, 1H); 8.29−8.18 (m, 2H); 7.86 (dd, 1H, J=8.2 and 12 Hz); 7.58−7.11 (complex mixture; 3H); 6.98−6.71 (complex mixture, 2H); 4.91 and 4.85 (2s, 2H) and 3.84 and 3.58 (2 s, 3H); 3.18 and 3.04 (2 s, 3H) ppm.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.[OH-].[Na+].CCO>C1(C)C=CC=CC=1.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>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Reactant: OCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(CO)cc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2.80 g (9.36 mmol) of 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Step B) and 4-bromobenzyl alcohol (5.25 g, 3 equiv) in toluene (125 mL) was added 1.25N NaOH (32 mL), EtOH (86 mL) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 3 mol %). The mixture was stirred at 100° C. under N2 for 3 hours. The reaction was concentrated and the residue was extracted with ethyl acetate. The organic solution was washed with 1N NaOH, H2O and brine. Next, the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to provide the titled compound; Rf =0.42 (1:1 EtOAc-hexane).
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]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=276.2 (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 phenylacetylene.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)[CH3:2].Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][CH2:8][C:6]1[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCc1ccc(C=O)s1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCc1ccc(CNCCC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A mixture of 5-ethyl-thiophene-2-carboxaldehyde (14.25 g, 101.6 mmol) and 3-amino-propionic acid tert-butyl ester hydrochloride (22.2 g, 122 mmol) in DCM was stirred for 3 hr at RT. Sodium triacetoxyborohydride (30.1 g, 142.2 mmol) was added in portions and the reaction was stirred for 2 h, at which point TLC indicated the completion of the reaction. To the reaction mixture was added a saturated aq solution of sodium bicarbonate, and then the phases were separated. The aqueous layer was extracted with DCM two times. The combined organic extracts were dried over sodium sulfate, concentrated under vacuum and the resulting material was purified on a silica gel column (eluent: hexanes→2% hexanes in EtOAc→5% hexanes in EtOAc→10% hexanes in EtOAc→20% hexanes in EtOAc→50% hexanes in EtOAc) to give 3-[(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (8.91 g, 32.6% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Reaction time: 0.33 h

Procedure:
To a solution of 80.0 g (0.452 mol) of 2,6-diisopropylaniline in 2000 cm3 of glacial acetic acid, 23.3 ml (72.3 g, 0.452 mol) of bromine were added dropwise, while vigorously stirring, over 20 minutes. This mixture was stirred additionally for 2 hours at 40° C. The white precipitate that formed was filtered off, washed with 100 ml of acetic acid, and dried in air. The resulting white solid was added to a solution of 150 g of potassium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The product was extracted with 3×100 ml of methyl-tert-butyl ether. The combined organic fractions were washed with Na2SO4 and evaporated to dryness. Fractional distillation gave a yellowish oil, b.p. 112-115° C./1 mm Hg. Yield 48.8 g (42%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclohexyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (Example 4b) and C-(3-trifluoromethyl-1,2,4-oxadiazol-5-yl)-methylamine (CAN 944905-93-5) as starting materials; MS (ESI) 453.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]>C1COCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CCl)c(F)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCNCC2)c(F)c1
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to 70° C. and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) was added. The suspension was heated at 70° C. overnight. The solid (piperazine) was filtered off, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the title compound (6 g, 92%). ESI-MS m/z [M+H]+ 213.04.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:16]1[CH:17]=[C:18]([O:19][CH3:20])[C:13]([O:12][CH3:11])=[CH:14][C:15]=1[CH2:21][C@H:22]([NH2:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: NC(=O)CCC(=O)NI
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1cc(OC)c(OC)cc1I
Yield: 84.3 %

Procedure:
To a solution of N-iodosuccinamide (8.3 g, 37 mmol) in 80 mL of dry acetonitrile were added (S)-3-(3,4-dimethoxyphenyl)1-methoxy-1-oxopropan-2-amine hydrochloride (4.63 g, 16.8 mmol) and trifluoroacetic acid (2.7 mL, 37 mmol) with stirring. The reaction mixture was stirred at room temperature in a 250 mL round bottom flask protected from light for 2 and half hours. The acetonitrile was removed and the remaining solid was taken up into water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 using saturated sodium bicarbonate solution. The neutralized aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield (S)-3-(2-Iodo-4,5-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-amine (5.17 g, 98%) as a pale yellow oil. The crude product was dried over dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:19]([O-:22])(=O)=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=1.[Na+].P(Cl)(Cl)([Cl:26])=O.CN(C)C(=O)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:19]([Cl:26])(=[O:22])=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=1
Reactant: Cc1cc(S(=O)(=O)[O-])ccc1N=Nc1ccc(O)c(C#N)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Cl)ccc1N=Nc1ccc(O)c(C#N)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
12.5 g (0.037 mol) of the sodium benzenesulfonate obtained in Step (a) above was stirred in 74 ml of acetonitrile, to which were added dropwise 14 ml of phosphorus oxychloride and then 14 mol of N,N-dimethylacetamide, and the mixture was heated at 50° C. with stirring for 1.5 hours. After cooling, the reaction mixture was added to 300 ml of ice water and the crystals thus-precipitated were collected by filtration. Yield: 11.9 g (96%).