Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[C@@H:16]([C:17]#[N:18])[NH:15][C:14]1=[O:19].C(N(CC)CC)C.Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])([CH3:46])[CH3:45])[C:39](Cl)=[O:40])[N:37]=1)=[O:31]>O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36]([C:38](=[N:42][O:43][C:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=2)=[O:48])([CH3:45])[CH3:46])[C:39]([NH:12][C@H:13]2[C@@H:16]([C:17]#[N:18])[NH:15][C:14]2=[O:19])=[O:40])[N:37]=1)=[O:31]
Reactant: N#C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(ON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
In 12 ml of tetrahydrofuran was dissolved 0.30 g of (3S, 4S)-3-amino-4-cyano-2-azetidinone p-toluenesulfonate. To the solution were added, under ice-cooling, 0.12 g of triethylamine and, subsequently 0.60 g of 2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was purified on a silicagel column [ethyl acetate-chloroformmethanol (3:3:1)] to yield 0.27 g of (3S, 4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18](/[CH:22]=[CH:6]/[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][CH:8]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: COc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 110 °C

Procedure:
7.1 mL of 3-methoxybenzaldehyde (58 mmoles), 9.953 g of 7-chloroquinaldine (56 mmoles) and 50 mL of acetic anhydride were mixed together and heated at 110° C. for 16 hours. After hydrolysis on ice, the product was extracted with ethyl acetate, washed with 5% sodium bicarbonate and brine and partially purified by flash chromatography using 10% ethyl acetate in hexane. Recrystallisation from ether: hexane yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:37])(=[O:36])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:17][CH:16]=3)[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9]2)=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:3]=1.[C:46](Cl)(=[O:49])[CH2:47][CH3:48].[H-].[Na+]>C1COCC1>[C:32]([O:31][C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:46](=[O:49])[CH2:47][CH3:48])=[CH:3][C:4]=3[C:42]([F:43])([F:44])[F:45])[C:12]2=[O:13])=[CH:20][CH:19]=1)(=[O:36])=[O:37])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCCc1nn(-c2ccc(N)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccc(NC(=O)CC)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1

Procedure:
This material is prepared from 2-[4-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 22) and propionyl chloride in the presence of sodium hydride in THF. The crude product is flash chromatographed over silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:24][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(OC1CCCCO1)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
To a solution of methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (2.2 g), dihydropyran (2.3 ml) and ethyl ether was added a catalytic amount of para-toluene sulfonic acid. The reaction was stirred at room temperature for four days. The ethyl ether was removed in vacuo and the remaining oil was purified by HPLC on silica gel using 7:93 ratio of ethyl acetate/hexanes as an eluent (1.8 g., 67% yield). In like manner as above, using appropriate starting materials, the following compound was made:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1>C(OCC)(=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([CH2:13][NH:12][C:1](=[O:3])[CH3:2])[CH2:23][CH2:22]2
Reactant: COc1ccc2c(c1)CCC(CN)C2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
Acetyl chloride (0.67 g) was added to a pyridine solution (15 ml) of 2-aminomethyl-6-methoxytetralin hydrochloride (1.5 g; obtained in Reference Example 11), and the reaction mixture was stirred at room temperature for 16 hours, to which was added ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (960 mg).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([C:19]#[N:20])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: N#C[Cu]C#N
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C#N)c2[nH]c(=O)n(C)c12
Yield: 85.1 %

Procedure:
A mixture of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (300 mg, 1.01 mmol) and copper cyanide (116 mg, 1.30 mmol) in 1-methyl-2-pyrrolidone (3 mL) was irradiated by microwave (200 w) at 150° C. for 1 h. After cooling, to the reaction mixture was diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with 50% diisopropyl ether/n-hexane to give the title compound (209 mg, 86%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([CH2:27][C:28]([OH:30])=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:28](=[O:30])[CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of the product of Step B of Example 1, 0.484 g of 1-naphthylacetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.718 g of trans (+) N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-1-naphthalene-acetamide melting at 127° C. and then 0.655 g of the base were reacted to obtain 0.533 g of its hydrochloride melting at ≃240° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:24]1([C:30]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:43]1([C:30]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39]([N:12]4[CH2:11][CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)(=[O:40])=[O:41])=[CH:38][C:32]=3[O:31]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Fc1ccc(C2C=CNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (2.56 g, 12 mmol) was suspended in methylene chloride (150 ml). Ethyldiisopropylamine (4.2 ml, 25 mmol) was added and the solution was stirred for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.72 g, 10 mmol) was added and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silical gel (100 g, dichloromethane eluant). The product was stirred with n-hexane, filtered and dried to yield the sulfonamide as white crystals (3.86 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C[N:25]1CCOCC1.[OH-].[NH4+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([NH2:25])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (S)-2-benzyloxycarbonylamino-succinic acid-4-tert-butyl ester (20.0 g, 61.9 mmol) in CH2Cl2 (100 mL) at −10° C. in a salt/ice/water bath was added N-methylmorpholine (8.20 mL, 74.20 mmol). This was followed by dropwise addition of isobutyl chlorofomate (9.63 mL, 74.20 mmol), over 20 min. After 30 min of stirring at −10° C., ammonium hydroxide solution (28% w/w ammonia, 100 mL) was added portionwise over 5 min. The reaction mixture was stirred for another 8 h then followed by removal of the CH2Cl2 in vacuo. The remaining solution was extracted with EtOAc. The combined extracts were washed with 100 mL of each of the following: 5% citric acid, saturated NaHCO3, and brine. Drying and removal of solvents under vacuum gave crude oil which crystallized from Et2O/hexanes mixture. 3-benzyloxycarbonylamino-succinamic acid tert-butyl ester was obtained in 95% yield (19.0 g). MS (APCI) m/z 323.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][C:19]=3[O:29][CH3:30])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64].Cl>C(Cl)Cl>[Cl:28][C:24]1[CH:25]=[CH:26][C:27]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[C:19]([O:29][CH3:30])[CH:18]=[CH:17][CH:16]=3.[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64]
Reactant: COc1cccc2c1Oc1cc(Cl)ccc1N2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(Cl)ccc1N2C1CCNCC1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1p, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound 3-chloro-6-methoxy-10-piperidin-4-yl-10H-phenoxazine, 7p was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[CH2:48]1
Reactant: O=C=Nc1cccnc1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2cccnc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 93 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatopyridine as the starting materials in 93% yield. LCMS for C29H29ClN9O2 (M+H)+: m/z=570.0.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[N:23]1([C:29](=[O:31])[CH3:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[C:29]([N:23]1[CH2:28][CH2:27][N:26]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:25][CH2:24]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml) and DIPEA (0.28 ml, 1.60 mmol) and 1-(piperazin-1-yl)ethanone (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (341 mg, 95% yield) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH:24]([CH2:31]Br)[C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:24]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:31]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC
Reactant: CC(C)NC(=O)C(Br)CBr
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(=O)NC(C)C)cc1OC

Procedure:
In a manner similar to Preparation 23, react N-(3-chlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromo-N-(1-methylethyl)propanamide to obtain the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].Br[C:44]1[CH:45]=[N:46][C:47]([N:50]2[CH2:53][CH:52]([OH:54])[CH2:51]2)=[N:48][CH:49]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:44]3[CH:45]=[N:46][C:47]([N:50]4[CH2:53][CH:52]([OH:54])[CH2:51]4)=[N:48][CH:49]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: OC1CN(c2ncc(Br)cn2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1ccc(-c2cnc(N3CC(O)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C

Procedure:
A heavy-walled glass vial was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (13 mg), 1-(5-bromopyrimidin-2-yl)azetidin-3-ol trifluoroacetic acid salt (18 mg), Cs2CO3 (18 mg), water (0.1 mL), and 1,4-dioxane (1 mL). The mixture was sparged with N2 for 10 min before PdCl2[1,1′-bis(diphenylphosphino)ferrocene] (2 mg) was added. The mixture was sparged with N2 for 10 min and then heated in a microwave oven at 110° C. for 30 min. After cooling to room temperature, the reaction mixture was purified by preparative HPLC to afford the title compound as its trifluoroacetic acid salt as an oil. Yield: 12.1 mg (89% of theory); LC (method 5): tR=1.3 min; Mass spectrum (ESI+): m/z=503 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.26 (s, 3H), 1.56 (d, 3H), 2.16 (s, 2H), 2.23 (m, 1H), 2.47 (m, 2H), 3.05 (m, 1H), 4.07 (m, 2H), 4.49 (m, 2H), 4.73 (m, 1H), 5.57 (q, 1H), 7.09 (d, 2H), 7.25-7.40 (7H), 8.63 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:17]1[CH:18]=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:9]([O:13][C:14]([N:16]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:17]1[CH:18]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Brc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
A solution of p-bromoiodobenzene (9.44 g, 33.4 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solution of 1.6M butyl lithium-hexane solution (19.0 ml, 30.3 mmol) in tetrahydrofuran (50 ml) at -78° C. in a nitrogen stream over 15 minutes. The resulting reaction solution was stirred at -78° C. for 40 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (5.0 g, 15.2 mmol) in tetrahydrofuran (17 ml) was added dropwise thereto over 10 minutes. The reaction solution was stirred at -78° C. for 1.5 hours. After addition of saturated aqueous ammonium chloride, the reaction solution was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel Column chromatography (Wakogel™ C-300, 200 ml ethyl acetate-heptane 2:3→3:2) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(4-bromophenyl)hydroxymethyl]pyrrolidine (6.30 g, yield: 85.3%) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C=O)C>[C:15]([O:19][C:20](=[O:21])[NH:22][CH2:23][CH2:24][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
Next, to a solution of 4-fluorophenol (0.47 g, 4.18 mmol) in DMF (10 mL) was added cesium carbonate (2.72 g, 8.36 mmol) at room temperature. The mixture was stirred at ambient temperature for 15 minutes, then methanesulfonic acid 2-(tert-butoxycarbonylamino)ethyl ester (1.00 g, 4.18 mmol) was added. The reaction mixture was stirred at 100° C. for 16 hours. Water was added and the mixture was concentrated in vacuo. Product mixture was dissolved in ethyl acetate and was washed with water, then with brine. The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane=7:1 to 4:1), and obtained [2-(4-fluorophenoxy)ethyl]carbamic acid tert-butyl ester as yellow oil (0.61 g, 57.4% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>CN(C=O)C>[CH:23]1([CH:13]([N:12]2[C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[N:7][C:2]([N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[CH:3][CH:4]=2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCNCC
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(-c2ccc(Cl)nc2)nc2ccccc21
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cn1
Temperature: 120 °C

Procedure:
90 mg of 2-[2-(6-Chloro-pyridin-3-yl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide (example 189) (0.2 mmol, 1 equiv.) were dissolved in DMF (1 ml). 102 ul (1 mmol, 5 equiv.) of diethylamine are added. The mixture was heated to 120° C. for 15 min using microwave heating). The product was isolated via preperative HPLC. MS (ES+): 489 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13]>C(OC(=O)C)C>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:12]([NH:11][CH3:10])=[O:13])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(O)c(Cl)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 4 -amino-2-chlorophenol (21.5 g; 0.15 mol) in ethylacetate (400 ml) is cooled to 0° C. and then methyl isocyanate (18.6 g; 0.15 mol) added slowly. The solution is stirred for one hour and then evaporated under vacuum to afford 30 g of title product, m.p. 188°-189° C.