Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[CH3:33][O:25][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][CH:29]=[N:30][C:22]=1[CH2:21][C@@H:11]1[O:10][C:9]([CH3:32])([CH3:31])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)C(Cc2ncccc2C(=O)O)OC1(C)C
Solvent: CCCCCC
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cccnc1C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(R)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (11 g, 25 mmol) in 200 mL of benzene and 30 mL of methanol is added a 2M solution of trimethylsilyl-diazomethane in hexane (16 mL, 32 mmol). The reaction is allowed to stir for 1 hour at RT after which time the solvent is removed under reduced pressure. Purification of the resultant residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CCN(C(C)C)C(C)C.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(NCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (0.5 g, 3.1 mmol) in EtOH (10 mL) was added Hunig's base (1.1 mL, 6.1 mmol) followed by benzylamine (0.37 mL, 3.35 mmol) and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (670 mg) as a yellow solid. LC-MS (ES) m/z=235 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1>CN(C=O)C>[Cl:54][C:55]1[C:60]([C@H:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)=[CH:59][C:58]([F:66])=[CH:57][N:56]=1
Reactant: Fc1cnc(Cl)c([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCO3 (20 mL), water (20 mL) and brine (3×20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68%). MS (apci pos) m/z=390.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C1COCC1>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[C:2]([NH:1][S:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=3)(=[O:26])=[O:25])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccnc1Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of EXAMPLE 2 in pyridine (9 mL/g) at 0° C. was treated with a mixture of para-methoxybenzenesulfonyl chloride (1.05 equivalents) in THF (1.4 mL/g) at 0° C. at a rate which kept the reaction temperature below 5° C., warmed to 25° C., stirred for 15 minutes, and concentrated. The concentrate was treated with n-propanol to provide a composition having 9% pyridine in the solvent mixture and to precipitate a solid. The mixture was cooled to 0° C. and filtered. The filtrant and washed with ethyl acetate (5-7 mL/g starting material) and dried at 45° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH:9]([CH2:15][CH:16]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[C:5]([CH3:20])[CH:4]=1)#[N:2].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([O:29][CH3:30])[CH:23]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]2[C:6]2[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:20])=[C:24]([O:29][CH3:30])[CH:23]=1
Reactant: CCOC(=O)C(CC=O)C(=O)c1ccc(C#N)cc1C
Reactant: COc1cc(Cl)ccc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C#N)cc1C
Temperature: 50 °C

Procedure:
To a solution of Intermediate C (2.5 g, 9.2 mmol) and 4-chloro-2-methoxyaniline (1.8 g, 9.2 mmol) in anhydrous EtOH (20 mL) was added PPTS (0.46 g, 0.18 mmol), and the reaction mixture was heated at 50° C. for six hours. Followed work-up procedure described in Step 1, Scheme 1 to give the desired compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCCCC(=O)O1
Reactant: Nc1c(F)c(F)cc(F)c1S
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 25.5 %

Procedure:
A solution of adipic acid (10.0 g, 68 mmol) in acetic anhydride (50 ml) was heated to reflux for 3 hours. An excess of acetic anhydride was then distilled off in vacuo leaving adipic anhydride (7.4 g). 2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in NMP (1 ml) under a nitrogen stream. To the resultant solution was gradually added adipic anhydride (143 mg, 1.1 mmol) and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 5-(4,5,7-trifluorobenzothiazol-2-yl)pentanoic acid (81 mg, 26%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.C([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=C>O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:1]([C:16]1[CH:17]=[CH:12][N:13]=[CH:14][CH:15]=1)=[CH2:2]
Reactant: C=Cc1ccc(O)cc1
Reactant: C=Cc1ccccn1
Solvent: O
Product: C=Cc1ccccc1
Product: C=Cc1ccncc1

Procedure:
Corresponding method-wise to example 1, 4-VP was used as cationic comonomer. Additions of vinylpyridine in 20 ml purest water via the injection pump: (11) 0.195 g or (12) 0.389 g or (13) 0.585 g or (14) 0.78 g or (15) 0.975 g—latices no. 11—no. 15 in Tab. 1.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[CH3:20][CH2:21][O:22][C:23]([CH:25]([N:34]1C(=O)O[C:36](=[O:37])[CH:35]1[CH3:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24].Cl>ClCCl.O>[CH3:20][CH2:21][O:22][C:23]([C@@H:25]([NH:34][C@H:35]([C:36]([N:1]1[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C@@H:4]2[C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:37])[CH3:41])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24]
Reactant: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Reactant: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
(2S,3aR,7aS) octahydro-1H-indole-2-carboxylic acid (65 gms 0.384 moles) was stirred in dichloromethane (200 ml), triethyl amine (30 ml) was added under stirring at ambient temperature for 30 mins. N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine N-carboxy anhydride (110 gms; 0.378 moles) (residue from Step A) dissolved in dichloromethane (50 ml) was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (500 ml) was added and the reaction mass was cooled to 15° C., pH of the reaction mass was adjusted to 4.2 using 2N HCl. The organic layer was separated and aqueous layer reextracted with dichloromethane. The combined organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum to get 50 gms of Trandolapril (HPLC purity 99.5%)
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1>C1COCC1>[O:20]([CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1)[Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: OC(c1nccs1)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(c1nccs1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
TBDMSCl (3.5 g, 23.2 mmol) and DBU (3.5 mL, 23.2 mmol) were added to a solution of 2-(1-hydroxy-1-cyclopropylmethyl)thiazole (3.0 g, 19.4 mmol) in dry THF (40 mL). The mixture was stirred at rt for 16 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography using 5% EtOAc/hexane to give 4.97 g (95%) of 2-(1-t-butyldimethylsiloxy-1-cyclopropylmethyl)thiazole as a colorless oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[NH:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44](Br)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[N:25]([CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCC(Br)CC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)[nH]c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)n(C3CCN(C)CC3)c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate (47 mg, 0.083 mmol) in DMF (1 mL), pyridine (0.5 mL), was added N-methyl-4-bromopiperidine (26 mg, 0.146 mmol). The reaction was stirred at 85° C. overnight. Then Cs2CO3 (54 mg) was added, raised temp to 100° C. and stirred overnight. More N-methyl-4-bromopiperidine (50 mg 0.28 mmol), the mixture was heated at 100° C. for 2 days. The reaction was quenched by adding water, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, first 0-100% EtOAc in hexanes to elute (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate , then switched to 0-20% MeOH in DCM to elute the product. LCMS-ESI+: calc'd for C36H41ClN4O4S: 661.2 (M+H+); found: 661.3.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)#[N:16]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1csc(N)n1
Agent: [Pb]
Product: CNC(=NCCSCc1csc(N)n1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-((2-amino-4-thiazolyl)methylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 3(b) gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([C:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([C:25]2([CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2SCC3)CC1
Yield: 52 %

Procedure:
8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.3 g, 0.719 mmol) in pyridine (3 mL) was reacted with 1-allyl-cyclopropane sulfonyl chloride (0.15 g, 0.863 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 0.21 g of the product (52% yield).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:17][C@@H:16]2[C:18](=[CH2:21])[CH2:19][CH2:20][C@@H:15]2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=[O:24])C.[C:26](#[N:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:6]([N:13]1[CH2:17][C@@H:16]2[C@:18]([NH:33][C:26](=[O:24])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH3:21])[CH2:19][CH2:20][C@@H:15]2[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: C=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: N#Cc1ccccc1
Agent: O=S(=O)(O)O
Product: C[C@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (1.437 mL, 27.0 mmol) was added to a solution of (3aS,6aS)-2-benzyl-4-methyleneoctahydrocyclopenta[c]pyrrole (0.575 g, 2.70 mmol, Example 1) in acetic acid (1.466 mL, 25.6 mmol) and benzonitrile (1.390 mL, 13.48 mmol) at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with ice, extracted with dichloromethane, and then purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.CN(C)[CH:17]=[O:18].[Cl-].[NH4+]>CCCCCC.C(OCC)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ccc(F)cc1F
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
2,4-Difluorobromobenzene (18.5 g) was added to dry diethyl ether (150 ml), cooled to -75° C. and n-butyllithium (61 5 ml of a 1.55 molar solution in hexane) was added under dry nitrogen over a period of 45 minutes. The mixture was stirred at -70° C. for a further 20 minutes and dry dimethylformamide (7.65 g) was added in dry diethyl ether (30 ml) at -70° C. over a period of 30 minutes. The mixture was stirred for 40 minutes and allowed to warm to -50° C. over a further 15 minutes. A solution of ammonium chloride (30 g) in water (100 ml) was added and the ether layer separated. The aqueous layer was further extracted with diethyl ether (2×50 ml) and the combined ethereal extracts were dried and evaporated to yield a pale yellow oil which was distilled at the water pump to give the desired product (13.0 g) b.p. 52°-55° C. at 14 mm Hg.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:18][C@@H:5]2[C@@:6]([CH2:16][F:17])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[NH:7][O:8][C@@H:4]2[CH2:3]1>CCCCCCC.C(O)C>[F:19][C:2]1([F:1])[CH2:18][C@H:5]2[C@:6]([CH2:16][F:17])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[NH:7][O:8][C@H:4]2[CH2:3]1
Reactant: FC[C@]1(c2ccccc2F)NO[C@@H]2CC(F)(F)C[C@@H]21
Solvent: CCCCCCC
Solvent: CCO
Product: FC[C@@]1(c2ccccc2F)NO[C@H]2CC(F)(F)C[C@H]21

Procedure:
Intermediate XXII-1: The racemate of (3S,3aR,6aR)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole was resolved on a chiral high-performance liquid chromatography (HPLC) column (Chiralpak AD) using n-heptane/ethanol (85:15) to give (3R,3aS,6aS)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as the faster eluting enantiomer and the desired (3S,3aR,6aR)-5,5-difluoro-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as the slower eluting enantiomer. MS: m/z=276.1 [M+H]+.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14]>[OH-].[Na+]>[CH2:4]([O:3][C:1]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
In a 2 L three-necked flask, L-alanine (54.0 g) is dissolved in 2N NaOH (305 mL) and cooled to 0° C. in an ice-bath. To this solution, carbobenzoxychloride (90 mL) and 2N NaOH (305 mL) are simultaneously added dropwise so that the reaction temperature does not exceed 5° C. After complete addition, the ice-bath is removed and the reaction mixture stirred for 2 hours at room temperature. Diethylether is added (100 mL) and the organic phase is separated. The aqueous phase is washed once more with Et2O (100 mL), and acidified to pH 1 with HCl (2N). Ethylacetate (150 mL) is added, and the organic phase is separated. The aqueous phase is extracted with AcOEt (3×150 mL), and the combined organic phases are washed with H2O (3×100 mL). After drying (MgSO4), the solvent is removed (20 Torr/30° C.) to leave a colorless oil, which crystallizes upon standing (110 g). Recrystallization (AcOEt/hexane) affords 100 mg (73%) of benzyloxycarbonyl-L-alanine, m.p. 85° C.; [α]23 =-14.3 (c=2 in AcOH).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([Si:23]([O:18][C:15](=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)[CH:16]=[CH2:17])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(=O)Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of 104 mL (104.0 mmol, 1.2 equiv.) of a 1.0M solution of potassium tert-butoxide in THF and 100 mL dry THF under nitrogen atmosphere at −78° C. was added a solution of 14.2 g (86.6 mmol, 1 equiv.) of 1-(4-fluorophenyl)but-3-en-2-one (step B) and 13.0 g (86.6 mmol) tert-butylchlorodimethylsilane in 100 mL dry THF. The reaction mixture was stirred at −78° C. for 6 hr and at RT for 6 hr then quenched by the addition of 50 mL water. The resulting mixture was warmed to RT, diluted with 150 mL hexanes, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with 50 mL brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under vacuum to give 20.5 g of the crude title compounds which were used without further purification. 1H-NMR (CDCl3): δ: 7.52 (2 H, m), 6.98 (2 H, m), 6.33 (1 H, dd, J1=13.2 Hz, J2=8.5 Hz), 5.97 (1 H, s), 5.52 (1 H, d, J=13.2 Hz), 5.17 (1 H, d, J=8.5 Hz).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccccc3OC(F)(F)F)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 2-trifluoromethoxybenzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A mixture of 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (309 mg, 0.84 mmol), ethynyl-trimethyl-silane (1.2 mL, 8.4 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 0.08 mmol), copper(I) iodide (32 mg, 0.16 mmol) and triethylamine (0.7 mL, 5.04 mmol) in 5 ml DMF was heated to 80° C. for 8 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, yield 62%). LCMS-ESI−: calc'd for C21H29N3O2Si: 383.56. Found: 384.1 (M+H+).