Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:10]=O.O.[H][H]>[Pd].CO>[CH3:10][N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([CH3:1])[C:7]([OH:9])=[O:8]
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN1CCC[C@@]1(C)C(=O)O
Yield: 100 %

Procedure:
A parr flask containing 2-methyl-L-proline (1.0 g, 7.7 mmol, 1.0 eq.), 40 mL of methanol, Formaldehyde 37 wt. % in water (2.1 mL, 77 mmol, 10 eq.), and Palladium 10 wt. % on Carbon (313 mg, 2.94 mmol, 0.38 eq.) was placed on a parr shaker and allowed to shake under 40 psi of hydrogen for ˜12 hours. Hydrogen was removed and the reaction was filtered through a pad of celite which was rinsed with a solution of 50% methanol 50% dichloromethane. Residue was concentrated in vacuo yielding #150 (1.1 g, 100%) as a white slight black colored solid. LC-MS (Protocol Q): m/z 144.0 [M+H+] retention time=0.17 minutes.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].FC(F)(F)C(O)=O.[C:12]1([CH2:18][CH2:19][CH:20]([NH:26][NH2:27])[C:21]([O:23]CC)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:35]([C@@H:40]1[CH2:44][S:43][CH:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[NH:41]1)([O:37][CH2:38][CH3:39])=[O:36]>C(Cl)Cl>[C:21]([CH:20]([NH:26][NH:27][C:1]([N:41]1[C@H:40]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:44][S:43][CH:42]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[OH:51])=[O:2])[CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:23])=[O:22]
Reactant: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(CCc1ccccc1)NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)NNC(CCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
An ice-cold solution of phosgene (1.1 M solution in toluene; 0.91 ml) was diluted with CH2Cl2 (3 ml) and then a solution of 56 (0.34 g, 1.0 mmol) and triethylamine (0.28 ml; 2.0 mmol) in CH2Cl2 (3 ml) was added slowly with cooling (ice-bath). Then a solution of 57 (0.25 g; 1.0 mmol) and triethyl amine (0.14 ml; 1.0 mmol) in CH2Cl2 (3 ml) was added and stirring was continued at room temperature for 6 hours. The reaction mixture was diluted with EtAc (25 ml) and extracted with H2O (2×10 ml) and brine, and dried (MgSO4). The residue after evaporation was subjected to chromatography on silica gel, allowing isolation of 58.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:10][CH3:11])[CH2:7][CH2:8][CH3:9])=[O:5].[CH2:16]([NH:18][CH2:19][CH2:20]C)[CH3:17].C12C(=CC=CC=1)[NH:27]C(=O)OC2=O>>[NH:27]1[CH2:20][CH2:19][N:18]=[C:16]1[CH2:17][NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:10][CH3:11])[CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNCC
Reactant: CCCN(CC)C(=O)c1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CCCN(CC)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-ethyl-N-propylbenzamide (prepared from N-ethylpropylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-Dihydro-1H-imidazol-2-ylmethyl)amino]-N-ethyl-N-propylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]#N)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[OH2:13].[OH-:14].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: N#Cc1cc(Cl)c2[nH]ncc2c1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 7-chloro-1H-indazole-5-carbonitrile (1.36 g, 7.66 mmol) in ethanol (52.5 mL) was added water (17.5 mL) and potassium hydroxide (6.44 g, 115 mmol). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature, extracted twice with ethyl ether, acidified the aqueous with 1N hydrochloric acid and the resultant precipitate was filtered to afford 7-chloro-1H-indazole-5-carboxylic acid as a brown solid (900 mg, 60%): −ESI MS (M−H) 195.2.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([NH:7][C:8]([C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=1)=[O:9])[CH2:5][CH3:6].[CH3:25]I>CS(C)=O>[CH3:25][N:7]([CH:4]([CH3:3])[CH2:5][CH3:6])[C:8]([C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=1)=[O:9]
Reactant: CCC(C)NC(=O)c1cc(-c2ccccc2)c2ccsc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 2, starting with dimethyl sulfoxide (24 cc), potassium hydroxide powder (3.6 g), N-(1-methylpropyl)-4-phenylbenzo[b]thiophene-6-carboxamide (4 g) and methyl iodide (1.6 cc). After chromatography of the residue over silica gel using a cyclohexane:ethyl acetate (50:50 by volume) mixture as the eluent and recrystallization in isopropyl ether, N-methyl-N-(1-methylpropyl)-4-phenylbenzo[b]thiophene-6-carboxamide (1.2 g), m.p. 84° C., is isolated.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:14]([O:16]CC)=[O:15])[CH3:2].[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)cnc2n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(C(=O)O)cc2cc(OC)cnc21
Reaction time: 0.01 h
Yield: 60.5 %

Procedure:
To a solution of ethyl 1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (60 mg, 0.24 mmol) in THF (2 ml) and MeOH (0.5 ml) was added lithium hydroxide (35 mg, 1.45 mmol) in water (2 mL). A cloudy solution formed which became clear after 30 s. The reaction mixture was allowed to stand at room temperature for 18 hr then concentrated under a stream of nitrogen. 2M HCl (2 ml, aqueous) was added to the crude product and the resulting solid filtered then dried under reduced pressure to give the title compound as an off-white solid (32 mg, 60%).
Reaction SMILES: C(OC(=O)[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([CH:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)(C)(C)C.Br[C:45]1[O:49][C:48]([C:50]([NH2:52])=[O:51])=[CH:47][CH:46]=1.C(Cl)Cl>C1COCC1.C(O)(C(F)(F)F)=O.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>[NH3:7].[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:7][C:8]3[C:9]4[N:10]([CH:27]=[CH:28][N:29]=4)[C:11]([C:45]4[O:49][C:48]([C:50]([NH2:52])=[O:51])=[CH:47][CH:46]=4)=[CH:12][N:13]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C)CC3)cc2)c2nccn12
Reactant: NC(=O)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)o4)n4ccnc34)cc2)CC1
Product: N
Yield: 21.9 %

Procedure:
In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.068 g, 0.162 mmol) in THF (3 mL), 5-bromo-furan-2-carboxylic acid amide (0.061 g, 0.324 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The crude reaction mixture is stirred in (1:1) TFA:DCM (2 mL) for 2 hours at room temperature. Purification of the crude by silica gel column chromatography, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH), affords the title compound (7.4 mg, 11%). LCMS: Rt 1.81 min (99%) m/z (APCI) 418 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.53 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.28 (1H, d, 7.34 (1H, d), 7.58 (1H, br s), 7.82 (1H, s), 7.90 (2H, d), 8.02 (1H, br s), 8.15 (1H, s), 8.48 (1H, s), 9.62 (1H, s).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:21]([C:17]2[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=2)=[O:22])=[CH:26]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)c1

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-m-tolyl-methanone was prepared from phenanthridine, m-toluoyl chloride, and indole according to GP 2. Yield, 13%. 1H-NMR (CD3CN): δ=2.22 (s, 3H), 6.22 (dd, J=2.5 Hz, J=1.0 Hz, 1H), 6.41 (s, br., 1H), 6.75 (t, J=7.5 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 7.06-7.15 (m, 4H), 7.15-7.21 (m, 2H), 7.24-7.31 (m, 2H), 7.43 (ddd, J=J=7.3 Hz, J=1.2 Hz, 1H), 7.47-7.59 (m, 2H), 7.88 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 7.93-8.00 (m, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.90 (s, br., 1H); (+)-ESI-MS: m/z=415 [M+H]+, 298 [M-indole+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[F:18][C:17]1([F:19])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:3]=1)[O:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10]2
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncnc4)cc32)C(F)(F)COC1
Yield: 12 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with pyrimidin-5-ylboronic acid yielded the title compound (12% yield). MS (ISP): m/z=423.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C(=O)C(C3C=CC=CC=3)=CN(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:32]1(=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][C:34](=O)[CH2:33]1.[C:41](O)(=O)[CH3:42]>>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:8]3[N:7]=[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:32](=[O:40])[C:33]4=[CH:10][C:9]=3[C:41]3[CH:42]=[CH:14][CH:13]=[CH:12][CH:17]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: O=C1CCCCC(=O)C1
Reactant: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCCC4)cc2)CCC1
Temperature: 100 °C
Yield: 24 %

Procedure:
To a solution of tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (119 mg, 0.28 mmol) in acetic acid (1 mL) was added molecular sieves (10 mg) and cycloheptane-1,3-dione (36 μL, 0.42 mmol) under nitrogen. The resulting mixture was heated at 100° C. for 2 h. After cooled down to room temperature, the mixture was partitioned between water (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase extracted into dichloromethane (2×10 mL). The combined organic phases were washed with saturated NaHCO3 solution (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 20% EtOAc in hexane) to give the title compound (32 mg, 24%). 1H NMR (500 MHz, CDCl3): 8.09 (1H, s), 7.38 (2H, d), 7.30 (2H,d), 7.25-7.24 (3H, m), 7.19-7.17 (2H, m), 5.04 (1H, br s), 3.29 (2H,t), 2.87 (2H, t), 2.60-2.25 (4H, m), 2.07-2.01 (3H, m), 1.99-1.94 (2H, m), 1.84-1.75 (1H, m), 1.42-1.15 (9H, br).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl>C1COCC1.C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:45][CH2:46][CH:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: NCC1CCOCC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Stir a stir solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (19.0 g, 51.43 mmol) in anhydrous THF (250 mL) cool to 5° C. under N2 add N-methylmorpholine (5.8 mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stir the mixture for 1 h and add a solution of 4-aminomethyltetrahydropyran (6.6 g, 57.34 mmol) in dry THF (75 mL) by dropping funnel. Warm the mixture to room temperature and stir for 3 h. Cool the mixture to 5° C., add 1N HCl (250 mL) and partition the resulting solution with ethyl acetate (250 mL). Extract the organic layer with aqueous saturated sodium bicarbonate (250 mL), brine (250 mL), and dry over sodium sulfate. Concentrate to give a foam, dissolve in minimum methylene chloride and add to a flash 65 M cartridge. Elute with 3:2 hexanes/ethyl acetate to give the major product as a solid, filter from hexanes, and dry (20 mm Hg, 40° C.) to give the homogeneous white solid (20.5 g, 85%); MS(ESI) m/z 467 (m+H).
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:5]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:23]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCC(C)C)CC2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(CC(C)C)C(=O)c1ccccc1Cl)CC2
Reaction time: 0.25 h
Yield: 51 %

Procedure:
TEA (1.4 ml, 10.1 mmol, 2.5 eq) was added dropwise at 0° C. to a solution of (R)-methyl 3-(isobutylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-08) (1.0 g, 4.04 mmol, 1 eq) in dichloromethane (25 ml), and stirring was carried out for 15 min. Then 2-chlorobenzoic acid chloride (0.61 ml, 4.858 mmol, 1.2 eq) was added at that temperature, and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (75 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and purified by column chromatography (silica gel, 2% MeOH in dichloromethane). Yield: 51% (800 mg, 2.078 mmol).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1.C[O:21][B:22](OC)[O:23]C.O>C1COCC1>[BH:22]([OH:23])[OH:21].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Agent: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OBO
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
(Method G-2) Under an atmosphere of nitrogen, n-butyllithium (22.75 mL, 2.2 eq) was slowly added to a solution of 4-chloropivaloylamino benzene (16.5 g, 0.078 mol) in dry THF (360 mL) at 0° C. After 2 hrs the mixture was cooled to −78° C. and trimethylborate (19.5 mL, 2.2 eq) slowly added. The mixture was allowed to warm to −15° C. and stirred for 2.5 hrs giving a clear colourless solution. Water (90 mL) was added, the lower, aqueous layer removed, washed with dichloromethane (150 mL) and acidified (90 mL 2M HCl) giving the title compound as a white solid (12.6 g, 0.049 mol, 63.2%). See, for example, Timari et al, 1996.
Reaction SMILES: C([Mg]Cl)(C)C.CON(C)[C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11].[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:23]1=2.Cl>C1COCC1.O>[O:22]1[C:23]2[CH:31]=[CH:30][C:29]([C@@H:9]([OH:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:11])=[CH:28][C:24]=2[O:25][CH2:26][CH2:27]1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccc2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol) was added to a suspension of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) keeping the temperature below −10° C. (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. 1N HCl (300 mL) was cooled on ice bath to +10° C., the reaction mixture was poured into the acidic water solution and extracted with TBME=tert-butyl methyl ether. The ether phases were washed with water, brine and dried (Na2SO4). Filtration and evaporation of solvents afforded a crude product as a slightly yellow oil that was purified by flash chromatography using TBME:Heptane=1:2 as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[BH4-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[S:4][C:3]=1[CH2:17][OH:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cn2)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cn2)sc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]thiophene-2-carbaldehyde (intermediate 78, 0.144 g) in tetrahydrofuran (10 ml) and water (15 ml) was treated with sodium borohydride (0.03 g). The reaction was stirred at room temperature for 30 minutes, extracted with ethyl acetate and the organic layer washed with water and dried with brine and over magnesium sulfate. The title compound was isolated after removal of the desiccant and evaporation of the solvent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][C:63]([F:66])([F:65])[F:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][C:63]([F:66])([F:65])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 105 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 99 mg light yellow viscous oil (66%). MS (ISP) 495.5 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11](=[O:17])[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1>[C:1]1([C:7]2[O:8][C:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:10][C:11](=[O:17])[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)C1=C(c2ccccc2)OC(c2ccccc2)CC1=O
Solvent: c1ccccc1
Product: CNC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O

Procedure:
A mixture of 10.0 grams (0.0324 mole) of 5,6-dihydro-2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, 11.0 grams (0.0485 mole) of dichloro dicyanoquinone and 200 milliliters of benzene is refluxed for 18 hours. The mixture is cooled and the precipitate filtered and washed with benzene and methylenedichloride. The filtrate is evaporated to dryness and the residue is partitioned between methylenedichloride and 2N sodium hydroxide and the layers separated. The organic layer is washed with 2N sodium hydroxide, water and 50 percent brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in a hot 50:50 mixture of ethanol:methanol, treated with decolorizing charcoal, filtered and evaporated in vacuo. The residue is crystallized from ethanol to give 2,6-diphenyl-N-methyl-4-oxo-4H-pyran-3-carboxamide, m.p. 196° C.-197° C.
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1.O>[CH2:46]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]1[CH:26]=[CH:25][C:24]2[NH:20][CH:21]=[N:22][C:23]=2[CH:28]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(Nc2ccc3c(c2)ncn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN(c2ccccc2)c2ccc3[nH]cnc3c2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N1-Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml; 3 mmol; 1.2 eq.). Benzylbromide (3 mmol; 1.2 eq.) was added and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml). After heating to reflux overnight the mixture was poured into saturated NaHCO3-solution and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.046 g (6.2%); MS m/z: 300.1 [M+H]+; 1H-NMR, 500 MHz, 1H-NMR (500 MHz, DMSO d6): δ 5.00 (s, 2H); 6.70-6.73 (m, 1H); 6.78-6.79 (m, 2H); 7.06-7.08 (m, 1H); 7.10-7.13 (m, 2H); 7.18-7.21 (m, 1H); 7.29-7.31 (m, 2H); 7.36-7.37 (m, 3H); 7.54 (d, 1H, 3J=8.5 Hz); 8.30 (s, 1H); 12.32 (br s, 1H); HPLC (METHOD [A]): rt 15.47 min (95.1%)