Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[OH:26])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:21]1)=[O:26]
Reactant: OC(c1cccs1)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1cccs1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve oxalyl chloride (1.23 g, 9.67 mmol) in methylene chloride (100 mL), place under an argon atmosphere and cool to -78° C. Add dimethylsulfoxide (1.43 mL) and stir for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethyl)-4-piperidinyl]-2-thiophenemethanol 8.06 mmol) in methylene chloride (100 mL). Stir at -78° C. for 30 minutes, then add triethylamine (6.07 mL). Stir at -78° C. for 30 minutes, remove the ice bath and allow to warm to room temperature. Evaporate the solvent in vacuo and partition between methylene chloride and water. Separate the organic phase and extract the aqueous phase with methylene chloride. Combine the organic phases, wash with water and dry (MgSO4). Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as a white crystalline solid; mp 77°-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25]C(OC(C)(C)C)=O)[C:8]1=[O:33])=[O:5])[CH3:2].Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[NH2:25][CH:9]1[N:10]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1=[O:33]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (3RS)-1-ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H -1,4-benzo-diazepin-2-one (7.2 g) in methanol (100 ml) was added 4N solution of hydrogen chloride in ethyl acetate (55 ml) under stirring at ambient temperature. The mixture was stirred for 4 hours under the same condition and allowed to stand overnight. The solvent was removed in vacuo to give residue, to which was added water. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined extract was washed with water and dried over magnesium sulfate. Removal of the solvent afford (3RS)-3-amino-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (5.46 g) as an amorphous mass, which was used in a following reaction step without further purification,
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:40][C:37]1[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: OCc1ccncc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
A solution of 5.5 g (21.72 mmol) of 1,1′-azodicarbonyl-dipiperidine, in solution in 15 ml of dry toluene, is added, under argon at 20° C., dropwise, to a solution of 3 g (14.48 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 2.37 g (21.72 mmol) of 4-pyridylcarbinol and 5.45 ml (21.72 mmol) of n-tributylphosphine in 200 ml of toluene. The mixture is stirred at 20° C. for 48 h. The reaction mixture is subsequently concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent: heptane/ethyl acetate). 3.2 g of the expected product are thus isolated, which product is used as it is in the subsequent synthesis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC=C(C(=O)OC)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1ccccc1CBr
Temperature: 90 °C
Yield: 97.3 %

Procedure:
20.6 g of the methyl α-(2-methylphenyl)-β-methoxyacrylate obtained as described in method A, 17.65 g of N-bromosuccinimide, 0.2 g of azobisisobutyronitrile and 150 ml of CCl4 are slowly heated to 90° C. and kept at this temperature until all of the succinimide floats on the solvent. The mixture is filtered, the filtrate is evaporated down, and the oil which remains is dissolved in about 5 ml of acetone and brought to crystallization with n-hexane. 27.5 g of colorless crystals of melting point 86°-87° C. are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[N:14]O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>C(Cl)(Cl)Cl.[Pt]=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:13])[NH2:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CC(C)N)cc1

Procedure:
1-(4-Carbomethoxyphenyl)propan-2-one oxime (10.0 g) in absolute alcohol (200 ml) and chloroform (25 ml) was hydrogenated on a Parr hydrogenator at 50 psi and at 50° in the presence of platinum oxide (250 mg) until hydrogen uptake had ceased. The catalyst was removed and the residue was recrystallised as the hydrochloride from methanol/ethyl acetate, mp 206°-210° (8.5 g). γ(d6DMSO) 8.84 (3H, d, 6 Hz), 6.2-7.5 (3H, m), 6.17 (3H, s), 2.59 (2H, d, J=8 Hz), 2.09 (2H, d, J=8 Hz), 1.50 (2H, br).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-])=O)=[CH:10][C:6]=1[C:7]([O-:9])=[O:8].[Na+].NN>[Ni]>[CH3:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)[O-]
Agent: [Ni]
Agent: NN
Agent: [Na+]
Product: COc1cc(N)c(N)cc1C(=O)O

Procedure:
reacting methyl-2-methoxy-4-acetylamino 5-nitrobenzoate with sodium hydroxide and then reducing the resulting sodium 2-methoxy-4-amino-5-nitrobenzoate intermediate with hydrazine in the presence of Raney nickel at ambient pressure to form a 2-methoxy-4,5-diaminobenzoic acid intermediate;
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C@@H:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:14]([F:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>>[F:17][C:14]1[CH:13]=[C:12]([CH:18]([CH3:19])[CH3:20])[C:11]2[C:10]([C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])=[C:9]3[C@@H:5]([CH2:4][C:3]([OH:2])=[O:21])[CH2:6][CH2:7][N:8]3[C:16]=2[CH:15]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(C(C)C)cc(F)cc12
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc3ccccc3c1)c1n2CC[C@@H]1CC(=O)O

Procedure:
Starting from methyl[(1R)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 44A, Step 1) and 2-naphthoyl chloride, the title compound was synthesized following the procedures described in Step 1′ of Example 61 and Step 10 of Example 7.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C.O.CC(=O)OCC.CC(=O)OCC.CCCCCC>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][S:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Fc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
4.9 g (35.8 mmol) of K2CO3 were added to a solution of 2.5 g (16.3 mmol) of 2-mercapto-nicotinic acid in DMF (40 ml), and the mixture was stirred for 30 min at RT. 3.5 g (16.3 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were then added and stirring was carried out for a further 72 h at RT. The mixture was then diluted with water and EA and adjusted to pH 5-6 with 5M acetic acid. The organic phase was separated off, washed with water, dried over MgSO4, filtered and concentrated in vacuo. CC (EA/hexane 1:2→5:1) of the residue yielded 2.2 g (7.6 mmol, 47%) of 2-(3-(4-fluoro-phenyl)propylthio)nicotinic acid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (154 mg, 0.23 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.72 ml, 9.35 mmol) was added. The orange reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (1.2 ml) and ethylenediamine (1.0 ml, 14.8 mmol) was added. The solution was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washing with water (hot), ethyl acetate and dichloromethane then dried under high vacuum to afford 37 mg (33%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=463; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.70 (br. s., 1H), 9.15 (s, 1H), 8.73 (d, J=8.7 Hz, 1H), 8.47 (t, J=7.4 Hz, 2H), 7.98 (s, 1H), 7.27 (d, J=8.7 Hz, 1H), 4.47-4.84 (m, 3H), 4.18 (s, 3H), 4.02-4.32 (m, 2H), 3.86 (br. s., 1H), 1.42 (d, J=4.5 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[N:55]1[CH2:59][CH2:58][CH:57]([C:60](O)=[O:61])[C:56]1=[O:63]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:60]([CH:57]1[CH2:58][CH2:59][N:55]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[F:48])[C:56]1=[O:63])=[O:61]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccccc2F)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccccc2F)C1=O
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.349 g; 0.672 mmol), N,N-diisoprpylethylamine (0.232 mL; 1.34 mmol) and 1-(2-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.078 g (44%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.C[O:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18](OC)OC.S(=O)(=O)(O)O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:18]=[C:17]2[CH2:16][C:15]([OH:23])=[O:14]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCC(OC)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 1.6 %

Procedure:
A mixture of 4-trifluoromethylphenylhydrazine (5 g), 4,4-dimethoxybutyric acid methyl ester (6 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 90° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained residue, and the mixture was heated to reflux for one hour. Water was added to the reaction mixture which was then rendered acidic with concentrated aqueous hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane, methanol, and acetic acid to obtain 0.11 g of the title compound as a colorless powder (1.5% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(Cl)Cl.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc2nc(-c3ccc(C=Cc4ccc([N+](=O)[O-])cc4)cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(C=Cc4ccc(N)cc4)cc3)sc2c1
Yield: 81.9 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-{4-[2-(4-nitrophenyl)-vinyl]-phenyl}-6-methylbenzothiazole (0.15 g, 0.403 mmol) and tin (II) chloride dihydrate (0.73 g, 3.22 mmol) in EtOH (5 ml) to give the title compound (0.113 g, 82%) as a pale yellow solid after work-up and flash chromatography (20:1 DCM/EtOAc).
Reaction SMILES: FC(F)(F)C1C=C(S([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=O)=O)C=CC=1.[CH:23](=O)[C:24]([CH3:27])(C)[CH3:25]>CC(C)=O>[CH2:25]([N:12]1[CH2:16][C@@H:15]2[C@@H:17]([NH:20][CH:18]([CH3:19])[CH3:17])[CH2:18][CH2:19][C@@H:14]2[CH2:13]1)[C:24]1[CH:27]=[CH:15][CH:14]=[CH:13][CH:23]=1
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C=O
Solvent: CC(C)=O
Product: CC(C)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
(3aR,4S,6aS)-2-Benzyl-N-isopropyloctahydrocyclopenta[c]pyrrol-4-amine was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 33 Step A for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and acetone for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.48 (d, J=7.5, 2H), 7.39 (t, J=7.5, 2H), 7.29 (t, J=7.3, 1H), 3.61-3.51 (m, 2H), 3.05 (dd, J=12.1, 5.4, 1H), 2.87-2.78 (m, 1H), 2.61-2.51 (m, 2H), 2.43-2.36 (m, 2H), 2.35-2.30 (m, 1H), 2.28-2.21 (m, 1H), 2.00-1.93 (m, 1H), 1.93-1.87 (m, 1H), 1.42-1.28 (m, 3H), 1.05-0.98 (m, 6H); MS (ESI+) m/z 259 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:25][N:26]([CH3:28])[NH2:27]>>[CH3:25][N:26]([CH3:28])[NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 60 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using N,N-dimethylhydrazine instead of 2,2,2-trifluoroethylamine, to the title compound (65 mg, 60%) which was obtained as a white solid. MS: m/e=361.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(O[C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][Si:27]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])(C3C=CC=CC=3)[CH2:26][CH2:25]2)=[CH:19][C:18]=1[F:43])(=O)=O>>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][Si@H:27]1[CH2:28][CH2:29][C@H:24]([C:20]2[CH:19]=[C:18]([F:43])[C:17]([CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([F:23])[CH:21]=2)[CH2:25][CH2:26]1
Reactant: CCCCCC[C@@H](F)CBr
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Product: CCCCCC[C@@H](F)Cc1c(F)cc([C@H]2CC[Si@H](CCCCCOC)CC2)cc1F

Procedure:
The general procedure of Example 18 was repeated using (R)-1-bromo-2-fluorooctane and (2,6-difluoro-4-(4-(5-methoxypentyl)-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH2:12][CH3:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCCl.ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:1][C:2]1[C:7]2[O:8][C:9]([CH2:12][CH3:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCc1oc2c(N)cccc2c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A mixture of 7-amino-2-ethyl-3-methylbenzo[b]furan (858 mg), 2,6-dichlorobenzoyl chloride (1.23 g) and triethylamine (1.23 g) in 1,2-dichloroethane (17 ml) was stirred for 3 hours at 70° C. The mixture was diluted with dichloromethane, washed with diluted hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo to give a solid. The residue solid was crystallized from a mixture of ethanol (20 ml) and water (2 ml) to give 7-(2,6-dichlorobenzoylamino)-2-ethyl-3-methylbenzo[b]furan (610 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: C[S@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[S@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.7 %

Procedure:
To a degassed solution of 2.0 mL DMF at room temperature containing (R)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31 mmol), 3-hydroxyphenylacetylene (73 mg, 0.62 mmol) and triethylamine (0.13 mL, 0.93 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I)iodide (3 mg, 0.016 mmol). The reaction was stirred at room temperature for 1.5 hours. Additional 3-hydroxyphenylacetylene was added (30 mg, 0.25 mmol) and the reaction was stirred at room temperature for an additional 3.5 hours. After proceeding for 5 hours the reaction was partitioned between EtOAc and H2O and the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and concentrated. The residual dark oil was purified by chromatography (silica gel, CHCl3/EtOAc) and the product containing fractions were concentrated. The resulting solid was triturated with EtOAc/hexane to give the title compound as an off-white solid (37 mg, 32%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23].O>CC(N(C)C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1-c1cnn(C)c1
Temperature: 150 °C
Reaction time: 12 h
Yield: 10.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (82.9 mg, 0.300 mmol) and (R)-2-amino-4-methylpentanamide (39.0 mg, 0.300 mmol) in DMA (2 mL) was stirred at 150° C. for 12 h. Water was subsequently added and the mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc) to give the title compound as a yellow oil (11.7 mg, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]O)[CH:23]=1>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:23]=1
Reactant: OCc1cccc(-c2c(F)cccc2F)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(F)cccc3F)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and (2′,6′-difluorobiphenyl-3-yl)methanol. colorless oil (yield 60%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Temperature: 60 °C
Yield: 41.1 %

Procedure:
To a solution of methyl [2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.058 g; 0.147 mmol) in methanol (1.5 mL) was added a solution of sodium hydroxide 5 N (0.29 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure to furnish 0.023 g (42%) of the title compound as a white solid.