Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.CCN(C(C)C)C(C)C.ClC(O[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O>C(Cl)Cl>[CH2:40]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of (S)-(3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 40) (1.20 g, 2.2 mmol), DIPEA (1.50 mL, 8.6 mmol), and DCM (20 mL) was added benzyl chloroformate (0.40 mL, 2.8 mmol). The resulting mixture was allowed to warm to rt as the bath warmed. After 16 h, the reaction was eluted through a cartridge of silica gel (25 g) with DCM. The filtrate was concentrated in vacuo to give the title compound as a light yellow oil. MS (ESI pos. ion) m/z: 464.9, 466.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH3:11])[CH2:5]2.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:13]1[NH:12][CH:16]=[CH:15][N:14]=1)[CH:6]([CH3:11])[CH2:5]2
Reactant: O=Cc1ncc[nH]1
Reactant: CC1Cc2cc(Cl)ccc2N1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1Cc2cc(Cl)ccc2N1Cc1ncc[nH]1

Procedure:
Prepared analogously to Example 1, from 5-chloro-2-methyl-2,3-dihydro-1H-indole, imidazole-2-carboxaldehyde, zinc chloride and sodium cyanoborohydride in methanol. MS (ISP): 250.1 ([{37Cl}M+H]+), 248.2 ([{35Cl}M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>CN(C=O)C.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>[CH2:26]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1)[CH:25]=[CH2:24]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1ccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc2c1
Temperature: 120 °C
Yield: 0.6 %

Procedure:
To a solution of 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.025 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.083 g, 0.025 mol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine)Palladium (0) (0.029 g, 0.0025 mol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere, then cooled to r.t. Water was added to the reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was crystallized with ethyl acetate/hexane to give the title compound as brown solid (0.050 g, 55%). 1H NMR (DMSO-d6, 400 MHz): δ 3.52 (d, 2H, J=6.4 Hz), 5.07-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m, 1H), 7.10 (dt, 1H, J=8.4 Hz (o-coupling), 7.31 (d, 1H, J=8.4 Hz (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.05 (d, 1H, J=8.4 Hz (o-coupling), 8.17 (broad s, 1H) MS ES+ (361.05), HPLC (method 5) Rt=16.74 min.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@@H:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[NH:35][C:34]1=[O:42].C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O.ClCCl.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:30][CH2:31][CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[NH:35][C:34]3=[O:42])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@@H:18]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=c1[nH]c2ccccc2n1CCCI
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 65 °C
Yield: 11.9 %

Procedure:
A mixture of (S)-methyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (159 mg, 0.383 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (115.6 mg, 0.38 mmol, 1 equiv) and potassium carbonate (158.6 mg, 1.148 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using 5% methanol in dichloromethane and water. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude mixture was purified using preparatory thin layer chromatography in 7% methanol in dichloromethane. The purified extract was lyophilized to afford the title compound as a white solid (25 mg, <10%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (bs, 2H), 1.84 (bs, 2H), 2.46 (bs, 4H); 2.50-2.51 (m, 4H); 3.74 (s, 3H); 3.85 (t, 2H, J=7.2 and 6.4 Hz); 4.15 (d, 1H, J=4.8 Hz); 4.80 (d, 1H, J=4.8 Hz); 5.89 (s, 1H)); 6.79-6.85 (m, 3H); 6.97 (d, 3H, J=2.8 Hz); 7.16-7.18 (m, 1H); 7.23 (t, 2H, J=7.2 and 8.8 Hz); 7.39-7.46 (m, 5H); 10.82 (s, 1H); MS for C32H35N5O4 m/z 554.11 (M+H)+.
Reaction SMILES: P([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])(OP(O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:29]>>[C@@H:14]1([N:16]2[C:25]3[C:19](=[C:20]([N+:22]([O-:29])=[CH:23][N:24]=3)[NH2:21])[N:18]=[CH:17]2)[O:15][C@H:11]([CH2:10][OH:9])[C@@H:12]([OH:27])[C@H:13]1[OH:26]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]

Procedure:
5′-Adenosine triphosphate N1-oxide with a purity of 98% or higher was obtained similarly as in the above procedure except for replacing the above adenosine 5′-diphosphate with adenosine 5′-triphosphate with a product code of P0756L, commercialized by New England Biolabs Japan Inc., Tokyo, Japan.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]3[NH:22][C:16]4[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[C:24]1([NH:23][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[C:6]([C:13]4[NH:22][C:16]5[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=5[CH:14]=4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Cl)nc34)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Nc5ccccc5)nc34)cc12
Yield: 15.1 %

Procedure:
To 6-(2-chloroquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one hydrochloride (Example 19b; 0.075 g, 0.225 mmol) and aniline (0.144 ml, 1.576 mmol) was added LHMDS (1.0 M in THF; 1.576 ml, 1.576 mmol). After 1 h the reaction was partitioned between saturated aq. NH4Cl and EtOAc. The aq. layer was washed with saturated aq. NH4Cl and 1× brine, dried over Na2SO4, and concentrated in vacuo. The solid residue from the separatory funnel was rinsed with 10% DCM/MeOH into an Erlenmeyer flask, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting solid was suspended in MeOH and filtered. The solid was collected to give 6-(2-(phenylamino)quinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.012 g, 0.034 mmol, 15% yield) as a dull-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (1H, br. s), 11.80 (1H, br. s.), 9.59 (1H, s), 8.13 (1H, d, J=9.0 Hz), 8.02 (1H, dd, J=7.4, 1.6 Hz), 7.88 (1H, s), 7.78 (2H, dd, J=8.6, 1.2 Hz), 7.67-7.73 (1H, m), 7.28-7.38 (3H, m), 7.09-7.19 (2H, m), 6.97-7.05 (1H, m). m/z (ESI, +ve) 353.9 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[C:2]1=[O:12].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][C:2]1=[O:12]
Reactant: O=c1[nH]c2ccccc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1Oc2ccccc2NC1Cl
Temperature: 130 °C

Procedure:
A mixture of 25 g of 4H-1,4-benzoxazin-2,3-dione and 14.3 ml of thionylchloride in 500 ml of toluene and 5 ml dimethylformamide was heated at about 130° C. until all solids dissolved (about 2-3 hours). The solution was decanted hot (if the solution was deeply colored, charcoal was added and following stirring, the solution was filtered) and the organic solution was evaporated to dryness to give 29 g of 3-chloro-4H-1,4-benzoxazin-2-one, m.p. 133°-136° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:28][F:29])[CH2:7][CH2:6][N:5]([C:8]2[C:17]([O:18][CH3:19])=[C:16]3[C:11]([C:12](=[O:26])[C:13]([C:23]([OH:25])=[O:24])=[CH:14][N:15]3[CH:20]3[CH2:22][CH2:21]3)=[CH:10][C:9]=2[F:27])[CH2:4]1.S(Cl)(Cl)=O.[CH3:34]O>>[NH2:1][CH2:2][C:3]1([CH2:28][F:29])[CH2:7][CH2:6][N:5]([C:8]2[C:17]([O:18][CH3:19])=[C:16]3[C:11]([C:12](=[O:26])[C:13]([C:23]([O:25][CH3:34])=[O:24])=[CH:14][N:15]3[CH:20]3[CH2:22][CH2:21]3)=[CH:10][C:9]=2[F:27])[CH2:4]1
Reactant: CO
Reactant: COc1c(N2CCC(CN)(CF)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(C2CC2)c2c(OC)c(N3CCC(CN)(CF)C3)c(F)cc2c1=O

Procedure:
7-(3-Aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (8.9 g) obtained in Example 1 was suspended in methanol (100 ml) and thionyl chloride (3.2 ml) was dropwise added with stirring under ice-cooling. After the dropwise addition, the mixture was refluxed overnight. Methanol and excess thionyl chloride were distilled away under reduced pressure. The residue was dissolved in water and the solution was made alkaline with potassium carbonate. The mixture was extracted twice with chloroform, dried and concentrated to dryness to give 9.8 g of the object compound, melting point 143°-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C@@H:29]([C:35]1[C:50]([CH3:51])=[CH:49][C:38]2[N:39]=[C:40]([C:42]3[CH:47]=[CH:46][N:45]=[C:44](Cl)[CH:43]=3)[S:41][C:37]=2[C:36]=1[C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([C:44]2[CH:43]=[C:42]([C:40]3[S:41][C:37]4[C:36]([C:52]5[CH:53]=[CH:54][C:55]([Cl:58])=[CH:56][CH:57]=5)=[C:35]([C@H:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:50]([CH3:51])=[CH:49][C:38]=4[N:39]=3)[CH:47]=[CH:46][N:45]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)nc2)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc(OCc5ccccc5)nc4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15 mg, 0.048 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (17 mg, 032 mmol) and 2M potassium carbonate solution (48 μL, 0.096 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes, Pd(PPh3)4 (3.7 mg, 0.0032 mmol) was added and reaction mixture was heated at 100° C. for 4 h. Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 20% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C39H37ClN3O4S: 678.2 (M+H+); Found: 678.3 (M+H+).
Reaction SMILES: [Na].[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([CH2:16][C:17]([OH:19])=O)[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:4]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C.N1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:17](=[O:19])[CH2:16][C:11]1[NH:12][C:13](=[O:15])[CH:14]=[C:9]([N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH3:2])[CH2:4]2)[N:10]=1
Reactant: Clc1cccc2c1CCN2
Reactant: CC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)N3CCc4c(Cl)cccc43)n2)CCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.975 g of the sodium salt of [4-(2-methylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 1b, step 2b), 0.534 g of 4-chloroindoline, 0.57 ml of pyridine and 15 ml of DMF are placed in a round-bottomed flask, and then 0.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at ambient temperature for 72 hours. The reaction mixture is poured into 50 ml of water, with stirring, and then the solid formed is filtered off through sintered glass and washed 3 times with approximately 15 ml of water, washed with 10 ml of EtOAc and rinsed with twice approximately 5 ml of diisopropyl ether, and the resulting product is left to air-dry under a hood. 2-[2-(4-Chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylmorpholin-4-yl)-3H-pyrimidin-4-one is isolated (0.98 g) and characterized in the form of an off-white solid (yield 71%).
Reaction SMILES: C([O:3][C:4](OCC)(OCC)[O:5]CC)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:32])[CH2:29][Mg]Br)=[CH:24][CH:23]=1.BrCC(C1C=CC(C2C=CC(F)=CC=2F)=CC=1)C.Cl>C1COCC1>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:32])[CH2:29][C:4]([OH:5])=[O:3])=[CH:24][CH:23]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CC(C[Mg]Br)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CC(CBr)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2 g. of orthocarbonic acid tetraethyl ester are added to a solution of 2-(2',4'-difluoro-4-biphenylyl)-1-propylmagnesium bromide, prepared from 3.11 g. of 4-(1-bromo-2-propyl)-2',4'-difluorobiphenyl, in 40 ml. of THF and the mixture is stirred for 4 hours at 25°. Excess dilute hydrochloric acid is added slowly. The mixture is heated under reflux for 24 hours, allowed to cool and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:9].[Cl-].[Cl-].C([Al+2])C>ClCCCl.C(Cl)Cl>[O:5]=[C:4]1[O:6][C:1](=[O:7])[CH:2]2[CH:3]1[CH2:9][CH:8]2[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=CSc1ccccc1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1OC(=O)C2C(Sc3ccccc3)CC12
Yield: 90.7 %

Procedure:
To a solution of maleic anhydride (0.39 g, 4 mmol) and phenyl vinyl sulfide (0.52, 4 mmol) in 17 mL of 1,2-dichloroethane under nitrogen, was added 2 mL (0.5 equiv) of ethylaluminum dichloride. The resultant solution was stirred at ambient temperature for 0.5 h and then diluted with 75 mL of methylene chloride. The methylene chloride solution was washed three times with saturated aqueous ammonium chloride solution and once with brine, dried over anhydrous sodium sulfate and concentrated to give 0.85 g of the title compound; EI-MS, m/e (rel intensity): 234 (M+, 23), 136 (100), 109 (12), 91 (21).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(Cl)[Cl:40].[ClH:43]>C(OCC)C>[ClH:40].[ClH:43].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:34]([N:35]([CH3:37])[CH3:36])=[O:38])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To the product from Step A (0.080 g, 0.155 mmol) was added chloroform (1.6 mL) To the resulting solution was added hydrogen chloride (0.387 mL, 1.55 mmol, 4.0 M in 1,4-dioxane) causing the solution to turn yellow. The mixture was stirred at ambient temperature for 3 hours. Additional hydrogen chloride (0.387 mL, 1.55 mmol, 4.0 M in 1,4-dioxane) was added and the reaction stirred at ambient temperature for another 3 hours. The mixture was diluted with diethyl ether (5 mL) and filtered. The product was washed with Et2O and dried in vacuo to provide 0.068 g (86%) of the desired product as a yellow solid. MS ESI (+) m/z 417.1 (M+1) detected.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]2)=[C:5]([NH2:21])[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])=[N:32][C:31]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])=[N:32][C:31]=1[C:42]([NH:21][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]1)=[O:43]
Reactant: Cn1ncc(N)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1N1CCC[C@H](N)C1
Yield: 13 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 107 as a white solid (36 mg, 13%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.29 (dd, J=8.6, 7.0, 1H), 7.51-7.25 (m, 6H), 3.62 (d, J=13.9, 3H), 3.19-3.06 (m, 1H), 2.96 (dt, J=18.1, 10.4, 2H), 2.81 (d, J=9.0, 1H), 2.69 (dd, J=16.1, 7.5, 1H), 1.75 (dd, J=24.8, 8.7, 2H), 1.63-1.45 (m, 1H), 1.14 (dd, J=19.8, 9.2, 1H). ESIMS m/z=416.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:19](=[O:21])[CH3:20])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15]C(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:47])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)([C:51]([F:54])([F:53])[F:52])=O>C(Cl)Cl>[N:41]1([C:37]2[CH:36]=[C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:47])[NH:24][C:9]5[CH:10]=[C:11]([C:51]([F:54])([F:53])[F:52])[C:12]([O:14][CH2:15][C:51]([F:54])([F:53])[F:52])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)[CH:40]=[CH:39][N:38]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(N4CCOCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M288) (423 mg, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (214 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1

Procedure:
tert-butyl 2-(formyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate was prepared according to the procedure outlined in Example 1, (Step 3). Starting from tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (1.0 g 3.7 mmol) in methylene chloride (100 ml) and active MnO2 (5 g, excess), 800 g (81% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 268.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][N:4]=[C:3]1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Cn1cncc1-c1ccccc1
Agent: [Li]CCCC
Product: Cn1c(-c2ccccc2)cnc1C=O

Procedure:
Using the procedure of Example 1D, 640 mg of 1-methyl-5-phenylimidazole, 1.55 ml of 2.6M n-butyllithium and 0.31 ml of dimethylformamide gave 320 mg of the desired product.