Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: C[C@@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.54 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 257-2 (5.50 mmol, crude form) as starting materials, respectively 0.76 g (Isomer A, colorless powder) and 0.60 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: O[C:2]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2(O)CN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (1.1 g, 3.9 mmol) in DCM (15 mL) at 0° C. was added triethylsilane (5 mL, 31 mmol) followed by TFA (1 mL, 13.8 mmol). The reaction mixture was allowed to warm to rt and stirred overnight. The mixture was then diluted with a satd. sodium bicarbonate solution and extracted with DCM (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude product which was purified by silica gel chromatography eluting with 10% ethyl aceate in hexane to give pure tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate (380 mg, 1.37 mmol, 34.8% yield). LCMS (Method 107): (ES-API), m/z 264.0 (M+H) RT=2.128 min; 1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 2H), 6.96-6.87 (m, 2H), 4.27-4.17 (m, 2H), 3.82-3.69 (m, 6H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:31])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH2:24][NH:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:6][CH:5]=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[Cl:1][C:2]1[N:3]([CH3:31])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[Cl:32])(=[O:41])=[O:40])=[O:18])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH2:24][NH:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27])=[CH:6][CH:5]=2
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cc1c(Cl)n(C)c2ccc(CCNC(=O)N(C)C)cc12
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1c(Cl)n(C)c2ccc(CCNC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[2-chloro-5-[2-(N',N'-dimethylureido)ethyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (94%) as a white solid: mp 204°-206° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:3].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>ClCCl>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:22])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane (3.00 mL, 12.00 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720 mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is allowed to stir for 1 hour. The reaction is quenched with 10% aqueous citric acid and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (148.2 mg). HPLC retention time=1.64 minutes (condition A); MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.21 (t, J=7.07 Hz, 3 H) 2.31-2.39 (m, 2 H) 2.40-2.56 (m, 4 H) 2.77-2.92 (m, 2 H) 4.08 (q, J=7.24 Hz, 2 H) 4.33-4.48 (m, 1 H) 6.62 (d, J=8.34 Hz, 1 H) 7.30 (d, J=8.08 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.41-7.49 (m, 2 H) 7.54-7.60 (m, 2 H) 7.60-7.67 (m, 2 H) 10.02 (br. s., 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:56]1([C@@H:62]([NH2:64])[CH3:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:64][C@H:62]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:63])=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.0 mg) and 1-hydroxybenzotriazole (20.1 mg) were dissolved in N,N-dimethylformamide (0.8 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41.9 mg) was added and the mixture was stirred at room temperature for 2 hours. Subsequently, (1S)-1-phenylethylamine (14.5 μL) was added and the mixture was further stirred at room temperature for 16.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (2 mL). The dichloromethane solution washed sequentially with 0.1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The solution then was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:ethyl acetate) to give ((2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-[(1S)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (51.5 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:20])=[N-]>>[CH3:20][O:12][C:11](=[O:13])[C@@H:10]1[CH2:14][CH2:15][CH2:16][N:9]1[C:7](=[O:8])[CH:6]([CH3:17])[CH2:5][S:4][C:1](=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)C(C)CSC(C)=O

Procedure:
1-(3-Acetylthio-2-methylpropanoyl)-L-proline is reacted with an ethereal solution of diazomethane according to the procedure described in Example 3 to obtain 1-(3-acetylthio-2-methylpropanoyl)-L-proline methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.NN>CCO.O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc3cc(N)cnc3[nH]2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred suspension of 6-Nitro-2-(4-nitrophenyl)-3H-imidazo [4,5-b]pyridine (4) (0.5 g, 1.75 mmol) in EtOH (40 mL) was added Raney Ni° (1 g, slurry in H2O) followed by hydrazine hydrate (2 mL) dropwise over 5 minutes. The reaction mixture was stirred at room temperature until the reaction subsided and was then heated at 100° C. for 1 h. The hot solution was filtered through celite and the filtrate concentrated under reduced pressure. Water was added to the residue resulting in the formation of an off white solid that was collected by filtration, rinsed with H2O and air dried. The solid was then dried in vacuuo at room temperature to give 5 as a light tan solid (0.318 g, 1.4 mmol, 81%) 1H NMR (500 MHz, DMSO-d6) δ12.27 (apparent d, 1H), 7.77 (br s, 2H), 7.70 (br s, 1H) 6.97 (br s, 1H), 6.63 (d, J=8.51 Hz, 2H), 5.57 (br s, 2H), 4.97 (br s, 2H)
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[N:14][S:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:1][C:2]([N:4]=[CH:17][N:18]([CH3:20])[CH3:19])=[S:3])[CH:6]=1)(=[O:12])=[O:13])[CH3:19]
Reactant: NC(=S)Nc1cccc(S(N)(=O)=O)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)Nc1cccc(S(=O)(=O)N=CN(C)C)c1
Yield: 82 %

Procedure:
A mixture of 2.3 g (9.9 mmol) 3-Thioureido-benzenesulfonamide and 17 ml N,N-Dimethylformamide dimethyl acetal was heated for 2 h to 90° C. The precipitate was filtered of washed with DCM/diethyl ether 1:3 and dried to yield 2.8 g (82%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18].O.O.Cl[Sn]Cl>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
The crude reaction mixture of 4-bromo-5-(2-isopropoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (as described below) was reduced in the presence of SnCl2.2H2O, in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.043 g, 0.14 mmol, 50% for three steps). LCMS m/z (%)=310 (M+H79Br, 99), 312 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.51 (s, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.76 (dd, J=2.7, 8.6 Hz, 1H), 6.62 (d, J=2.7 Hz, 1H), 4.08 (ddd, J=6.1, 6.1, 12.2 Hz, 1H), 3.74 (s, 3H), 1.21 (d, J=6.1 Hz, 3H), 1.01 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=1[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 164.7 %

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (22 g, 78 mmol), prepared as described in example 1, step b, 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (22 g, 86 mmol) and cesium carbonate (38 g, 117 mmol) in DMF (400 mL) was stirred at 80° C. for 3 h. After cooled to room temperature, the mixture was poured into 300 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over sodium sulphate and combined with a separate batch prepared similarly and then evaporated to give the crude product (55 g, 62%) as a yellow solid; LC/MS: MS (ES+) m/e 428 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 2.55 (s, 3H), 5.78 (s, 2H), 6.35 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (4.5 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and methyl chloroformate (4.5 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.20 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[C:4]([CH2:15][CH3:16])[CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(N(CC)CC)C.[Cu]I.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>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][C:4]=2[CH2:15][CH3:16])[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CCc1cc(Br)ccc1C1(OC(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OC(C)C)CC1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93, 300.0 mg, 1.07 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (20.0 mg, 0.11 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 mg, 0.11 mmol). The resulting reaction mixture was heated to 70° C. for Sd. The title compound (320.0 mg, 99%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]#[CH:15].C(N(CC)C1C=CC=CC=1)C>C(OCC)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]2[C:3]=1[O:12][CH2:13][CH:14]=[CH:15]2
Reactant: C#CCOc1cc(C(=O)OC)ccc1F
Solvent: CCOCC
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1ccc(F)c2c1C=CCO2
Temperature: 220 °C

Procedure:
Methyl 4-fluoro-3-propargyloxybenzoate (14.0 g, 67.2 mmol) was mixed with N,N-diethylaniline and the reaction was heated to 220° C. for 5 hours. The black reaction mixture was allowed to cool, dissolved in diethyl ether (600 mL) and washed with 2 M HCl in portions (1 L). The aqueous washings were re-extracted with diethyl ether, the combined ether phases were washed with H2O until neutral, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give a dark brown crude residue. The crude solid was chromatographed on silica (eluent: methylene chloride/carbon tetrachloride 1:1) to give 11.9 g (85% yield) of a tannish yellow solid as the title compound (mp 73.5-74.5° C.). EIMS (70 eV) m/z (relative intensity) 208 (65, M+), 207 (42), 194 (12), 193 (100), 177 (32), 149 (10), 148 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24](I)[N:23]=[C:22]2[CH:27]([CH3:29])[CH3:28])=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:24]2[N:23]=[C:22]([CH:27]([CH3:29])[CH3:28])[N:21]([C:18]3[CH:17]=[N:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(I)cn1-c1ccc(Cl)nc1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Product: CC(C)c1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=358.1 (M+H+), was prepared in accordance with the general method of example B, step 2, from 2-Chloro-4-trimethylsilanylethynyl-pyridine and 2-Chloro-5-(4-iodo-2-isopropyl-imidazol-1-yl)-pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:11][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: Cc1c(C(N)=O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
2-Methyl-3-nitrobenzamide (8.85 g) was dissolved in a mixture solvent of ethanol (300 ml) and tetrahydrofuran (200 ml), followed by addition of 10% palladium-carbon (800 mg). The resulting mixture was stirred under hydrogen atmosphere at ambient temperature and atmospheric pressure for 6 hours. After insoluble materials were filtered off, the filtrate was concentrated under reduced pressure and washed with isopropyl ether, to afford the entitled compound as white solid (6.73 g, 91%). The physico-chemical values are as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[S:25]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine in 100 ml DCM and 4 ml pyridine, 11.6 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 17.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19])=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To solution of (2,4-dichloro-phenoxy)-acetic acid (51 mg, 0.23 mmol), 2-amino isonicotinamide (47.66 mg, 0.34 mmol) and DMAP (56.6 mg, 0.46 mmol) in DMF 4 ml was added PyBOP (236 mg, 0.46 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 77% yield).
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[C:9]([CH2:19][OH:20])=[N:10][CH:11]=[C:12]([CH:14]2OCC[O:15]2)[CH:13]=1.CC(C)=O.[OH-].[Na+]>O>[Cl:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[N:10][C:9]=1[CH2:19][OH:20]
Reactant: OCc1ncc(C2OCCO2)cc1Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cnc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10 %

Procedure:
Oxalic acid (415 mg, 3.29 mmol) was added to a mixture of [3-chloro-5-(1,3-dioxolan-2-yl)-2-pyridinyl]methanol (142 mg, 0.659 mmol), acetone (7.5 ml), and water (7.5 ml) at room temperature and heated under reflux. After 2.5 h, HPLC showed full conversion. Cooled to rt, basified with 1M NaOH, extracted with TBME, dried (MgSO4), filtered and concentrated to give 139 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded impure product. Repurification by manual flash chromatography using a 1 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (11.3 mg, 10%) as a white solid.