Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].II.[CH2:15]([C:18](=[CH2:22])[C:19]([OH:21])=[O:20])[CH2:16][CH3:17].C(N(CC)CC)C.S(=O)(=O)(O)O>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](/[CH:22]=[C:18](\[CH2:15][CH2:16][CH3:17])/[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: C=C(CCC)C(=O)O
Reactant: COc1ccc(S(=O)[O-])cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC/C(=C\S(=O)(=O)c1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Sodium 4-methoxyphenylsulfinate (10.0 g, 51.49 mmol) was dissolved in water (50 ml). This solution was shaken with iodine (8.7 g, 34.29 mmol) in dichloromethane (60 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulfate and filtered into a flask containing 2-propylacrylic acid (2.0 g, 17.52 mmol). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (7.3 ml, 51.49 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. Sulphuric acid (2M, 50 ml) was added to quench the reaction. The organic phase was washed with 10% aqueous sodium bisulphite (50 ml), then extracted with sodium hydroxide (1 g) in water (50 ml). The aqueous layer was washed with MTBE (20 ml) and the acidifed with sulphuric acid (2M, 10 ml). The product was extracted into dichloromethane (2×30 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 90% yield. This yellow solid was recrystallised from hot solvent (ethyl acetate:heptane:glacial acetic acid 1:1:0.2) to give the title compound as white crystals (4.02 g, 80%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C:21](=[O:23])[CH2:20][C@H:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:13]=[CH2:14]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C:21]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:20][CH:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:13]=[CH2:14]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCOC(=O)N1CC(=O)C[C@H]1C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC(O)(C#C[Si](C)(C)C)CC1C(=O)OC
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of trimethylsilylacetylene (5 g) in tetrahydrofuran (60 ml) was added n-butyllithium (32 ml) slowly and dropwise at -50° C. After completion of the dropwise addition, the mixture was stirred at -50° C. for 30 minutes, at the end of which time a tetrahydrofuran solution (10 ml) of (2S)-1-allyloxycarbonyl-2-methoxycarbonyl-4-oxopyrrolidine (10 g) was added below -50° C. The mixture was stirred for 1 hour and, then, diluted with saturated aqueous ammonium chloride solution and ethyl acetate. After standing, the aqueous layer was separated and extracted with ethyl acetate twice and the organic layers were combined, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonyl-4-trimethylsilylethynylpyrrolidine (8.26 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65]>CN(C=O)C.O>[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][N:59]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]3[N:18]=[CH:17][N:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:20]=3)=[O:22])[CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66]
Reactant: Fc1ccc(OC2CCNCC2)cc1C(F)(F)F
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccc(F)c(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 49 %

Procedure:
DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (61 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) to afford 59.3 mg (49% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 96%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (m, 1H), 8.3 (m, 1H), 8.05 (m, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.4 (m, 4H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.4 (b, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:23])([CH3:22])[CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:21])(=O)C.[CH:24]1([NH:27][C:28](=[O:46])[C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]([CH3:44])=[C:31]([F:45])[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.O>[CH:24]1([NH:27][C:28](=[O:46])[C:29]2[CH:34]=[C:33]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:21])[N:8]([CH2:7][C:6]([CH3:22])([CH3:23])[CH2:5][OH:4])[CH:17]=[C:16]4[CH:18]=[O:19])[C:32]([CH3:44])=[C:31]([F:45])[CH:30]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)OCC(C)(C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 101.3 %

Procedure:
A solution of 3-(6-bromo-4-formyl-1-oxoisoquinolin-2(1H)-yl)-2,2-dimethylpropyl acetate (Example 1e, 0.25 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.28 g), Pd-118 (0.024 g) and potassium carbonate (0.31 g) under nitrogen. The resulting mixture was stirred at 70° C. for 6 h. Methanol (10 mL) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 100% ethyl acetate) to afford the subtitle compound (0.30 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)cc1

Procedure:
4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=471.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [N:1]1([CH2:6][C:7](C2C=CC(C#N)=CC=2)=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[H][H].C(O[CH2:33][CH3:34])(=O)C>[Pd]>[N:1]1([CH2:6][CH:7]([C:34]2[CH:33]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]#[N:1])[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(C)=O
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=Cc2ccc(C(F)(F)F)cc2)Cn2cncn2)cc1
Agent: [Pd]
Product: N#Cc1ccccc1C(Cc1ccc(C(F)(F)F)cc1)Cn1cncn1

Procedure:
A mixture of 4-[1-(1,2,4-triazol-1-ylmethyl)-2-(4-trifluoromethylphenyl)vinyl]benzonitrile (0.05 g, mixed E and Z isomers) and 10% by weight palladium-on-carbon (0.02 g) in ethyl acetate (5 ml) was stirred rapidly under an atomosphere of hydrogen at atmospheric pressure for 2h. The mixture was filtered, and the filtrate was evaporated to dryness, to give 4-([2-(1,2,4-triazol-1-yl)-1-(4-trifluoromethylbenzyl)ethyl]benzonitrile as a white solid, which was washed with ethyl acetate and dried, m.p. 123°.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+]=[N-].[C:19]([OH:22])(=S)[CH3:20]>>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:19](=[O:22])[CH3:20])[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: CC(O)=S
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (Intermediate 5, 5.00 g, 0.014 mol) was suspended in thioacetic acid (10 ml) and the solution was stirred under nitrogen at room temperature for ca. 16 h. The resulting suspension was concentrated under vacuum. The crude product was crystallized from methanol/acetone, then further purified by chromatography on silica gel using dichloromethane to give 3.71 g of the title product as a white solid.
Reaction SMILES: O.Br[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[C:14](=[O:17])([O-])[O-].[Na+].[Na+].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][N:8]1[C@H:7]2[C@@:20]([CH3:24])([C:20]3[CH:24]=[CH:4][C:3]([C:3]4[CH:4]=[C:5]5[C:9](=[CH:10][CH:11]=4)[NH:8][C:7](=[O:12])[C:6]5=[O:13])=[CH:11][C:21]=3[CH2:22][CH2:6]2)[CH2:21][CH2:22][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)C(=O)C(=O)N5)cc3CC[C@@H]12
Yield: 15 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 5-bromoisatin hydrate (159 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80 , under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 36 mg (15%) of the title compound as a white solid. mp >250° FDMS: m/e=374. α[D]589 =+75.33 (c=0.53, chloroform).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:21][Si:22]([CH3:25])([Cl:24])[Cl:23].[Cl:26][SiH:27]([Cl:29])[Cl:28]>>[Cl:26][Si:27]([Cl:29])([Cl:28])[CH2:21][Si:22]([Cl:24])([Cl:23])[CH3:25].[Cl:26][SiH:27]([Cl:28])[CH2:21][Si:22]([Cl:24])([Cl:23])[CH3:25]
Reactant: C[Si](Cl)(Cl)CCl
Reactant: Cl[SiH](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](Cl)(Cl)C[SiH](Cl)Cl
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 14 %
Yield: 58 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.75 mmol) of triphenylphosphine, 1.07 g (7.5 mmol) of (chloromethyl)methyldichlorosilane, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 24 hrs. The resulting mixture was distilled to give 1.0 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (bp; 181-182° C., yield; 58%) and 0.1 g of 1,1,3,3-tetrachloro-1,3-disilabutane (bp; 166-167° C., yield; 14%).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (75 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0° C. for 45 minutes a solution of 1-bromomethyl-4-chloro-2-fluorobenzene (2.6 g) in tetrahydrofuran (25 mL) was added and the resulting mixture stirred at room temperature for 17 hours. The mixture was diluted with water and the tetrahydrofuran removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:19 to 1:9 by volume) to afford title compound, 1.4 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][CH:11]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[C:12](=[O:35])[C:13](C#N)=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:42]=[O+][O-].[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[NH:10][CH:11]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[C:12](=[O:35])[C:13](=[O:42])[N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[O+][O-]
Reactant: C1CCNCC1
Reactant: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)C(=O)N1CCCCC1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A solution of [1-(acetylaminomethyl)-3-cyano-2-oxo-3-(triphenyl-λ5-phosphanylidene) propyl]carbamic acid benzyl ester (prepared as described in Example 10) (572 mg, 1.01 mmol, 1 equiv) in CH2Cl2 (11 mL) at −78° C. was treated with ozone gas for 2 h. The chilled solution was then purged with Ar for 10 min until the color had changed from green to yellow. Piperidine (0.110 mL, 1.12 mmol, 1.1 equiv) was added dropwise over 1 min, and stirring continued at −78° C. for 15 min. The volatiles were removed under reduced pressure, and the residue purified by flash column chromatography (5% CH3OH in CH2Cl2) to give [1-(acetylaminomethyl)-2,3-dioxo-3-piperidin-1-yl-propyl]carbamic acid benzyl ester (120.7 mg, 32% yield) as a colorless foam. Rf=0.30 (EtOAc). IR (cm−1) 3304, 1720, 1639, 1537. 1H NMR (CDCl3) δ1.59 (br s, 7H), 1.97 (s, 3H), 3.22-3.91 (m, 7H), 4.54-4.58 (m, 1H), 5.09 (s, 2H), 6.28 (br s, 1H), 6.67 (br s, 1H), 7.34 (s, 5H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>CC(C)=O>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:13][C:1](=[O:3])[CH3:2])=[S:12])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C(=S)NC(C)=O)cc1
Yield: 72.2 %

Procedure:
A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20 mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00 g, 29.9 mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). The reaction mixture was heated to reflux for 30 min then poured onto ice water. The resulting precipitate was isolated via filtration and dried under vacuum overnight to provide a light yellow/orange solid (4.52 g, 72%). 1H NMR (400 MHz, CDCl3) δ2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd, J=6.9, 2.0 Hz, 2H), (dd, J=6.9, 2.0 Hz, 2H).
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][CH:5]([F:28])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22](N(OC)C)=[O:23])=[N:14]1>C1COCC1>[C:22]([C:15]1[C:16](=[O:21])[C:17]([O:19][CH3:20])=[CH:18][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]([F:4])[F:28])[N:14]=1)(=[O:23])[CH3:1]
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
MeMgBr (1 M solution in THF, 40.4 ml, 40.4 mmol) was added dropwise at −78° C. to a solution of 1-[2-(difluoromethoxy)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.79 g, 13.48 mmol) in THF (500 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and warm to room temperature. The reaction mixture was concentrated under reduced pressure and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1-0/1) and recrystallized from diisopropyl ether/AcOEt to give the title compound (3.33 g, 80% yield) as colorless crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.68 (3H, s), 3.89 (3H, s), 6.55 (1H, t, J=72.7 Hz), 7.36-7.45 (2H, m), 7.50-7.57 (1H, m), 7.61 (1H, dd, J=7.8, 1.7 Hz), 7.72 (1H, s).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].[C:43]([C:46]1[CH:53]=[C:52]([Cl:54])[C:49]([C:50]#[N:51])=[C:48]([I:55])[C:47]=1O)(=[O:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([C:46]1[C:47]([O:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[C:48]([I:55])[C:49]([C:50]#[N:51])=[C:52]([Cl:54])[CH:53]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)c1cc(Cl)c(C#N)c(I)c1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(C#N)c(I)c1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
Diethyl azodicarboxylate (2.3 mL, 14 mmol) was added slowly to a solution of triphenylphosphine (3.79 g, 14.5 mmol) and tert-butyl (2-hydroxyethyl)carbamate (2.3 g, 14 mmol) in tetrahydrofuran (93 mL) and cooled in an ice bath. After stirring for 15 minutes, the 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile (3.1 g, 9.6 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 N HCl, and brine, then dried over magnesium sulfate and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate as a tan solid (3.2 g, 71%). LCMS calculated for C16H18ClIN2O4Na (M+Na)+: m/z=487.1; found: 486.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:24]([NH:36][CH:37]4[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]4)=[O:25])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: NC1CCN(CCO)CC1
Product: O=C(Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1)NC1CCN(CCO)CC1

Procedure:
The title compound was prepared from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine (Example 106) (240 mg, 0.818 mmol), 4-nitrophenyl chloroformate (165 mg, 0.818 mmol) and commercially available 4-amino-1-piperidine-ethanol (118 mg, 0.818 mmol) in accordance with the general method 4 described in example 170 step C and was obtained as an off-white solid (54 mg, 14%); MS: m/e=464.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[NH:13]C(=O)OC(C)(C)C)[CH2:8]1.[NH2:22][C:23]1[C:24]([C:30]([OH:32])=O)=[N:25][C:26](Br)=[CH:27][CH:28]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:21])[C:6]=2[N:7]2[CH2:8][CH:9]3[CH:11]([CH:10]3[NH2:13])[CH2:12]2)=[O:32])=[N:25][C:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[CH:27][CH:28]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: OB(O)c1ccccc1F
Reactant: Cn1ncc(N)c1N1CC2C(C1)C2NC(=O)OC(C)(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1N1CC2C(N)C2C1
Yield: 35 %

Procedure:
Following the procedures for Example 141, tert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate and 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 151 as a white solid (32 mg, 35%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.06 (t, J=7.8, 1H), 7.75 (d, J=8.5, 1H), 7.66-7.25 (m, 5H), 7.06 (s, 2H), 3.59 (s, 3H), 3.40 (t, J=10.6, 2H), 3.17 (d, J=8.5, 2H), 2.09 (s, 1H), 1.44 (s, 2H). ESIMS m/z=408.1 (M+1)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[CH:10]2.[CH3:17][C:18](N(C)C)=[O:19]>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:18](=[O:19])[CH3:17]
Reactant: CC(=O)N(C)C
Reactant: Cn1ccc2cc(F)ccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cn(C)c2ccc(F)cc12
Reaction time: 0.17 h

Procedure:
Phosphoryl chloride (1.1 ml) was added dropwise to ice-cooled dimethylacetamide (10 ml) and the resulting solution was stirred at ca.0° for 10 min. A solution of 5-fluoro-1-methyl-1H-indole (1.3 g) in dimethylacetamide (5 ml) was added, and the resulting solution was stirred at 100° for 2 h, then cooled, and partitioned between sodium carbonate (2N; 100 ml) and ethyl acetate (2×50 ml). The combined organic extracts were washed with water (50 ml), dried and evaporated in vacuo to give a solid which was purified by FCC eluting with hexane:ethyl acetate (1:1) to give the title compound (0.48 g), m.p. 158°-160°.