Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:7][C@H:8]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([C@@H:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:16])[CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=O)C=C.CC1(C)CC(=O)CC(=O)C1>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.C1COCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:20]([C@@H:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@H:8]([CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])[NH2:7]
Reactant: C=CCOC(=O)N[C@H](C(=O)Nc1cc([C@@H](C)CC(=O)OC(C)(C)C)ccc1Cl)C(C)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: CC([C@H](N)C(=O)Nc1cc([C@@H](C)CC(=O)OC(C)(C)C)ccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.39 g (2.74 mmol) of tert-butyl (3S)-3-[3-({N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorophenyl]butanoate (Example 41A, mixture of 4 isomers) and 3.08 g (21.9 mmol) of dimedone were initially charged in 9.4 ml of abs. THF. At RT, the solution was deoxygenated by passing through argon for 30 min Subsequently 63.4 mg (0.055 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at RT overnight. After dilution with ethyl acetate, the mixture was washed twice with sat. sodium bicarbonate solution and once with sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→20:1) and separated. This gave 950 mg of the target compound as diastereomer mixture 1 (81.9% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([CH:16](Br)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)[CH3:14].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]([CH3:14])[N:1]=[C:2]12
Reactant: Nc1nccc2c(Cl)cccc12
Reactant: CCOC(=O)C(Br)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c3cccc(Cl)c3ccn12
Yield: 59.1 %

Procedure:
A mixture of 1-amino-5-chloroisoquinoline (6.1 g), ethyl 2-acetyl-2-bromoacetate (10.75 g) and sodium bicarbonate (14.36 g) in ethanol (72 ml) was refluxed for 2 hours and then filtered by suction. The filtrate was evaporated in vacuo, and the residue was dissolved in a mixture of chloroform and methanol. The solution was treated with silica gel (10 g) and filtered by suction. The filtrate was evaporated in vacuo and the residue was recrystallized from ethanol to give 7-chloro-3-ethoxycarbonyl-2-methylimidazo[2,1-a]isoquinoline (5.83 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[O:21])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)=[O:27].CC(O)=O>CS(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[O:21])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[CH2:25][C:26](=[O:27])[CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:35])[CH2:30][CH2:29]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(CCl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CSc1nccc(C(=O)Cc2cccc(C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CSc1nccc(C(=O)C(CC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
Under Ar, a solution of 25 (4.0 g, 12.8 mmol) in DMSO (30 mL) was treated with 95% NaH (0.35 g, 13.8 mmol). After stirring at room temperature for 15 min, a solution of 5 (3.9 g, 13.2 mmol) in DMSO (20 mL) was added in one portion to the deep red solution. After stirring at room temperature for 18 h, 2N AcOH was added and then poured carefully in saturated Na2CO3. The basic aqueous solution was extracted with EtOAc (3×). The organic extracts were backwashed with H2O, brine, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (80 mm) and the product was eluted with 30% EtOAc-hexanes to yield 1.5 g of 26.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][OH:11]>C(O)C>[OH:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCCO
Solvent: CCO
Product: O=C1N=C(NCCO)CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (2.66 g) in ethanol (50 mL) was added 2-aminoethanol (1.22 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the precipitate was collected by filtration and washed with ethanol to give the title compound (2.24 g).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[OH:41][C@H:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 57.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[4-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6][C:5]=2[S:4][CH:3]=1.[NH4+].[Cl-:16]>CN(C=O)C.Cl[Cu]>[Cl:16][C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6][C:5]=2[S:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(Br)csc2[nH]1
Reactant: [Cl-]
Agent: Cl[Cu]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)csc2[nH]1
Yield: 86 %

Procedure:
To a solution of ethyl 3-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.25 g, 0.93 mmol) in DMF (37.5 mL) was added CuCl (178 mg, 1.85 mmol). The combined reactants were heated to reflux for 7 h, at which time the cooled mixture was diluted with a saturated solution of NH4Cl (20 mL) and extracted with Et2O (3×40 mL). The combined organic fractions were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification of the crude oil by flash column chromatography (25% EtOAc in hexanes) afforded ethyl 3-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.18 g, 86% yield).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[O:8][CH2:9][CH:10]([OH:29])[CH2:11][N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:25]([O:27]C)=[O:26])(=[O:4])[CH3:3].O.[OH-].[Li+].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(#N)C.O>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:2]([NH:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[O:8][CH2:9][CH:10]([OH:29])[CH2:11][N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:25]([OH:27])=[O:26])(=[O:4])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1CC(O)COc1ccccc1NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccccc1OCC(O)CN1C[C@@H](Oc2ccc(Cl)cc2)C[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
Compound (i) (50 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml) and water (3 ml). Lithium hydroxide hydrate (8 mg, 0.2 mmol) dissolved in water (0.5 ml) was added. The reaction was complete after 0.5 h as determined by analytical HPLC. The mixture was acidified with TFA and purified by preparative RP-HPLC using acetonitrile and water containing 0.1% TFA as mobile phase. The appropriate fraction was concentrated in vacuo and the residue lyophilized from acetic acid to give the title compound as a white amorphous solid (27 mg, 48%). The substance is a diastereomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH:12]([N:22]([CH3:21])[CH:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)[CH2:13][CH3:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2ccccc2C1
Solvent: CCN(CC)CC
Product: CCC(N1CCc2cc(OC)c(OC)cc2CC1=O)N(C)C1CCc2ccccc2C1

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 140°-142° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[O:3][C:4]1[CH:5]=[C:6]([CH:45]=[CH:46][CH:47]=1)[O:7][C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=[N:19][C:15]=2[CH2:14]1.FC(F)(F)OC1C=C(C=CC=1)OC1C=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1>C(O)(=O)C.O>[F:49][C:2]([F:1])([F:48])[O:3][C:4]1[CH:5]=[C:6]([CH:45]=[CH:46][CH:47]=1)[O:7][C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[NH:17][CH:18]=[N:19][C:15]=2[CH2:14]1
Reactant: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1
Agent: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cccc(Oc2ccccc2COCC2CCc3[nH]cnc3C2)c1
Temperature: 70 °C

Procedure:
A solution of a mixture of 5-[2-(3-(trifluoromethoxy)phenoxy)benzyloxymethyl]-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-[2-(3-(trifluoromethoxy)phenoxy)benzyloxymethyl]-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (600 mg, 0.91 mmol) in a mixture of acetic acid (9 ml) and water (1 ml) was heated to 70° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using DCM/methanol/−25% aqueous ammonia as eluent, to give 251 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([C:22]4[N:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[N:26]=4)[CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:13])=[C:9]([CH3:31])[C:8]=2[CH:32]=1)([CH3:3])[CH3:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.CO.C(O)(C(F)(F)F)=O>CC#N.CS(C)=O.CO.O>[CH3:31][C:9]1[C:8]2[CH:32]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[S:11][C:10]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28]([O:30][CH3:33])=[O:29])[N:26]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:13])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn(CC(=O)O)n3)c2)sc2ccc(C(C)C)cc12
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Cn1nnc(-c2cccc(NS(=O)(=O)c3sc4ccc(C(C)C)cc4c3C)c2)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
A reaction mixture containing [5-(3-{[(5-isopropyl-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}phenyl)-2H-tetrazol-2-yl]acetic acid (5.7 mg, 0.012 mmol) (Example 12), 1,1′-carbonyldiimidazole (4.0 mg, 0.025 mmol) and pyridine (5.0 μL, 0.062 mmol) in MeCN (0.60 mL) was stirred at room temperature for 25 min. MeOH (50 μL, 1.23 mmol) was added. The reaction mixture was stirred at room temperature over night, and then diluted with DMSO/MeOH/water. TFA was added and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 72% yield (4.2 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.28 (d, J=6.92 Hz, 6 H) 2.53 (s, 3 H) 3.02 (spt, J=6.92 Hz, 1 H) 3.82 (s, 3 H) 5.44 (s, 2 H) 6.92 (s, 1 H) 7.35 (ddd, J=8.11, 2.16, 1.28 Hz, 1 H) 7.35-7.38 (m, 1 H) 7.39 (dd, J=8.11, 7.50 Hz, 1 H) 7.53-7.55 (m, 1 H) 7.70 (d, J=8.42 Hz, 1 H) 7.90 (dd, J=2.16, 1.50 Hz, 1 H) 7.93 (ddd, J=7.50, 1.50, 1.28 Hz, 1 H). MS (ESI+) m/z 486 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]1.[C:17]([C:19]1[CH:20]=[C:21]([Sn](C)(C)C)[CH:22]=[N:23][CH:24]=1)#[N:18].C(N(CC)CC)C.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]2)[CH:22]=[N:23][CH:24]=1)#[N:18]
Reactant: C[Sn](C)(C)c1cncc(C#N)c1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(-c4cncc(C#N)c4)cc23)C1
Yield: 11.2 %

Procedure:
A mixture of 5-bromo-3-(N-methylpyrrolidin-3-yl)-1H-indole (0.500 g, 1.79 mmol), 5-cyano-3-trimethylstannylpyridine (0.525 g, 1.97 mmol, 1.1 eq), bis(triphenylphosphine)palladium(II) chloride (0.628 g, 0.90 mmol, 0.5 eq), triethylamine (1.19 mL, 8.59 mmol, 4.8 eq), lithium chloride (0.235 g, 5.55 mmol, 3.1 eq), and 2,6-di-tert-butyl-4-methylphenol (40 mg) in anhydrous acetontrile (5 mL) was heated at reflux under nitrogen for 20 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel (approx 50 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide] to afford the title compound (0.060 g, 0.20 mmol, 11%) as a clear, pale brown oil: LRMS (m/z, relative intensity) 302 (M+, 29), 245 (8), 57 (100); HRMS calculated for C19H18N4 302.1528, found 302.1533.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[C:34]4[CH2:37][CH2:36][CH2:35]4)[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
The product of Example 304F (0.285 g, 0.62 mmol) in N,N-dimethylacetamide (1.5 mL) was reacted with cyclobutanone (0.85 mL, 10.9 mmol) in a sealed tube in a microwave reactor at 130° C. for 45 minutes. The reaction was cooled to 25° C., concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. and the resulting residue was triturated with diethyl ether to give the title compound (0.178 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:16]2[CH:17]=[C:12]([CH2:11][OH:10])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCc1cccc(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCc1cccc(Cc2ccc(Br)cc2)c1
Yield: 85 %

Procedure:
4-Bromobenzyl bromide (6.1 g, 22 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (3.0 g, 20 mmol) were dissolved in a mixed solvent of toluene (40 mL), ethanol (30 mL) and water (20 mL), and tetrakis(triphenylphosphine)palladium (1.1 g, 1.0 mmol) and sodium carbonate (4.2 g, 40 mmol) were added under a nitrogen atmosphere, followed by heating to reflux for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.75 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (4.7 g, 17 mmol) as a yellow oil (yield 85%).
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3].[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C(N(CC)CC)C>[CH3:15][Si:16]([CH3:19])([CH3:18])[O:9][CH2:8][CH2:7][O:6][C:4](=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [O-2]
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCO[Si](C)(C)C

Procedure:
HEMA monomer (with an impurity level lower than 0.8% purchased from Rohm) was mixed with triethylamine (≧99.5% pure, from Fluka) and petrol ether (bp 40-60° C.) passed through aluminum oxide and reacted with trimethyl chlorosilane (≧99.0% pure, from Fluka) to obtain trimethylsilyloxyethyl-methacrylate (TMS-HEMA). TMS-HEMA was purified by distillation from calciumhydride (once) and triethylaluminum (electronic grade, from Aldrich) (twice).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:36])[CH2:35][CH2:34]2)[CH:30]=[C:29]([F:37])[C:28]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:44](=[O:45])[C:42]2[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:28]3[C:29]([F:37])=[CH:30][C:31]([C:33]4([OH:36])[CH2:34][CH2:35]4)=[CH:32][C:27]=3[F:26])[N:43]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 204. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.27 (dd, J=8.7, 4.0 Hz, 1H), 8.13 (t, J=8.9 Hz, 1H), 7.90 (s, 1H), 7.09 (d, J=9.8 Hz, 2H), 6.26 (s, 1H), 4.81 (dd, J=10.5, 3.7 Hz, 1H), 4.34-4.09 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.12-2.99 (m, 1H), 2.11-1.99 (m, 1H), 1.83-1.53 (m, 5H), 1.27-1.08 (m, 4H). LCMS (ES+) m/z 520 (M+1).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1)=[O:19]
Reactant: CN1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 2 h
Yield: 101.9 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 110 (0.26 g, 0.69 mmol) and Pd/C (0.50 g) in methanol (25 mL) was hydrogenated at 20 psi at room temperature for 2 hours. The mixture was filtered through a Celite pad and concentrated to provide 111 (0.20 g) as a white foam.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:23][CH:22]([C:24](OC)=[O:25])[CH2:21]2)=[CH:16][CH:15]=1.Cl>CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:21][CH:22]([C:24](=[O:25])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH2:23]2)=[CH:18][CH:19]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C1CC(c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C1CC(c2ccc(Cl)cc2)C1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (16.2ml. of a 1.23M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (2.48g.) in dry tetrahydrofuran (25ml.) at -78° C. in an atmosphere of argon. After 10 minutes, a solution of methyl 3-(4-chlorophenyl)cyclobutanecarboxylate mixed isomers (2.24g.) in dry tetrahydrofuran (25ml.) was added dropwise, and stirred at -78° C. for 2 hours. The reaction mixture was warmed to room temperature and neutralised by the addition of 1N hydrochloric acid (20ml.) to the stirred solution. The tetrahydrofuran was evaporated, and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was dried over sodium sulphate and the solvent was evaporated. The crude product was purified by dry column chromatography on "Kieselgel 60" (100g.) eluting with ethyl acetate, to give dimethyl 2-[3-(4-chlorophenyl)cyclobutyl]-2-oxoethylphosphonate, as a mixture of cis and trans isomers, RF = 0.35 and 0.40 (ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (δ values):