Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[C:71]([N:88]1[CH2:93][CH2:92][NH:91][CH2:90][CH2:89]1)([O:73][CH2:74][CH:75]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[C:81]2[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72]>C(#N)C>[CH:86]1[C:87]2[CH:75]([CH2:74][O:73][C:71]([N:88]3[CH2:89][CH2:90][N:91]([C:13](=[O:14])[C@@H:12]([N:11]([CH2:10][C:9]4[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=4)[C:23](=[O:36])[CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:92][CH2:93]3)=[O:72])[C:76]3[C:81](=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:82]=2[CH:83]=[CH:84][CH:85]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (1.5 g, 2.86 mmol) and TBTU (1.1 g, 3.43 mmol) was dissolved in acetonitrile (30 mL) and DIPEA (1.5 mL, 8.6 mmol) and stirred at rt for 5 min, followed by the addition of Fmoc-piperazine hydrobromide (1.22 g, 3.15 mmol). The reaction mixture was stirred at rt for 16 h and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 ml) and washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silicagel, EtOAc/heptane=3/7) to give 1.75 g (75%) of 4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester. LC-MS: tR=1.25 min; [M+H]+=814.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[CH:3][C:4]=1[CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cc1CCNC(=O)c1cc2ccccc2cc1O
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: COCCOC
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1CCNC(=O)c1cc2ccccc2cc1O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound N-2-(3-bromo-6-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide in 2.0 mL of DME were added 36.6 mg (0.3 mmol) of 4-nitrophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 22 mg of the title compound.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:26])[CH:7]=[C:8]([CH3:25])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])C>CC(O)C>[CH3:25][C:8]([CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:7][C:6]([OH:26])=[O:5]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Under argon atmosphere, potassium hydroxide (19.4 g) was dissolved in 2-propanol (200 ml) under reflux, and the solution was added dropwise with (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid ethyl ester (48.6 g) dissolved in 2-propanol (50 ml). After the mixture was stirred for 10 minutes under reflux, ice water was added to the reaction mixture and the aqueous layer was washed with n-hexane. The aqueous layer was made acid with 10% aqueous hydrochloric acid, and then extracted with diisopropyl ether. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain crude (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (35.7 g, purity: 62.2%) as orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:3]=1[C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=O.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:3]=1[C:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[N:6]=1
Reactant: COc1cc(Br)c(C(=O)NC(C)(C)CO)cc1OC
Solvent: O=S(Cl)Cl
Product: COc1cc(Br)c(C2=NC(C)(C)CO2)cc1OC

Procedure:
Reaction of 2-bromo-4,5-dimethoxy-N-(1-hydroxy-2-methyl-2-propyl)benzamide and thionyl chloride by the method described in Example 1b provides 2-(2-bromo-4,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless crystals, m.p. 49°-51°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[C:4]2[CH2:15][CH:16]([C:18]([O:20]CC)=[O:19])[O:17][C:3]=12>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[C:4]2[CH2:15][CH:16]([C:18]([OH:20])=[O:19])[O:17][C:3]=12
Reactant: CCOC(=O)C1Cc2cc3c(CC(C)C)noc3c(Cl)c2O1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Cc1noc2c(Cl)c3c(cc12)CC(C(=O)O)O3

Procedure:
The above was obtained by analogous treatment of 7c and recrystallization from ethyl acetate/hexane; m.p. 181°-183° C. Anal. (C14H14ClNO4) C,H,N,Cl.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].[OH-].[Na+].[Cl-].[Na+]>CS(C)=O>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NCCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of 17.1 g. (0.1 m.) of benzyl bromide in 100 ml. of dimethylsulfoxide is added slowly to a stirred mixture of 18.2 g. (0.1 m.) of 4-hydroxy-3-nitrophenethylamine in 1 l. of dimethylsulfoxide and 60 ml. of 2N sodium hydroxide at 85° C. After addition is complete the reaction mixture is stirred at 85° C. for an additional two hours, poured into ice-water, saturated with sodium chloride and extracted with ethyl acetate. The organic extract is dried and concentrated to give 4-benzyloxy-3-nitrophenethylamine. The latter (2.72 g., 0.01 m.) in 50 ml. of toluene is refluxed azeotropically with 1.27 g. (0.012 m.) of benzaldehyde until water formation is completed (about one hour). Solvent is removed by distillation to leave the crude imine. Sodium borohydride (0.38 g., 0.01 m.) is then added to a solution of the above imine in 30 ml. of methanol over a period of 30 minutes and after stirring for an additional hour the reaction mixture is evaporated. The residue is treated with 2N hydrochloric acid and ether. The solid obtained is filtered and washed to give N-benzyl-4-benzyloxy-3-nitrophenethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)O
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 1.15 ml of isopropanol were reacted to obtain 1.46 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+63.5°±3° (c=0.3% in benzene).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([OH:24])[CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[CH3:5].Br[C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[O:24][C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1)[CH3:5]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91 %

Procedure:
3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (340 mg, 1.03 mmol) synthesized in Example (107c) was dissolved in acetonitrile (10 mL), and 2-bromo-5-(methylsulfonyl)pyrazine (300 mg, 1.27 mmol) synthesized in Example (107d) and cesium carbonate (850 mg, 2.61 mmol) were added at room temperature, followed by stirring at room temperature for 4.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate=100%) to afford the desired compound (456 mg, yield 91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([Cl:34])[CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH:9]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:31]=[C:32]([Cl:34])[CH:33]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)COC1
Yield: 8 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 3,5-dichlorophenylboronic acid yielded the title compound (8% yield) as a white solid. MS (ISP): m/z=489.4 [M+H]+.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([C@H:39]1[O:41][CH2:40]1)Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][C@@H:39]1[CH2:40][O:41]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H]1CO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), potassium carbonate (62 mg), and (S)-epichlorohydrin (42 mg), and the mixture was stirred at 90° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give (S)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (33 mg, yield 54%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])([CH3:25])[CH3:24]>>[OH:30][CH2:29][CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(C)NCCCO
Product: CC(C)N(CCCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 3-(isopropylamino)propan-1-ol to give 290. MS: (ESI+)=413.1
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=[O:8].[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:12]([C:3]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH:11]=[CH2:10]
Reactant: O=C(O)C1CCCC1=O
Reactant: C=CCBr
Product: C=CCC1(C(=O)O)CCCC1=O

Procedure:
A lower alkyl ester of 2-oxocyclopentanecarboxylic acid is alkylated with allyl bromide to yield the lower alkyl ester of 1-(2-propenyl)-2-oxocyclopentanecarboxylic acid. Treatment with anhydrous ammonia yields the ester of 5-carboxy-oct-7-enoic acid amide. Treatment with thionyl chloride yields the ester of 5-carboxy-oct-7-enenitrile. The ester is reduced, e.g. with sodium borohydride to the corresponding alcohol. A reactive ester thereof, e.g. the methanesulfonyl ester is reacted with a diester of malonic acid and the resulting malonate ester is decarboxylated to yield the ester of 4-(3-cyanopropyl)-6-heptenoic acid which is then reacted with 3-bromopyridine under conditions of the Heck reaction to obtain the ester of 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoic acid which is hydrogenated under conditions known in the art, e.g. in ethanolic ammonia with rhodium on carbon catalyst, to the ester of 8-amino-4-[3-(3-pyridyl)-propyl]-octanoic acid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:10]1([NH:9][C:7]([C:3]2[N:2]([NH:1][C:27]([C:24]3([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]3)=[O:28])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C(=O)Nn2cccc2C(=O)Nc2ccccc2)CC1
Yield: 95.4 %

Procedure:
The title compound was prepared from 1-amino-N-phenyl-1H-pyrrole-2-carboxamide (0.30 g, 1.5 mmol) and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (0.30 g, 1.5 mmol) following the experimental procedure described in Preparation 73a. 0.55 g (91% yield) of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1CCOCC1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2C1CCOCC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol), dihydro-2H-pyran-4-(3H)-one (110 mg, 1.103 mmol), titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) and sodium triacetoxyhydroborate (514 mg, 2.427 mmol) in CH2Cl2 (8 mL) (10 mg, 3%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O2, 311.13; found 311.2.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:32][CH:31]=2)[C:25]([C:45]#[N:46])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:34][CH:35]=2)[C:25]([C:45]#[N:46])=[C:24]([O:20][CH2:19][C:17]2[N:18]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=3)[O:15][CH:16]=2)[N:23]=1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(Sc4ccccc4)c3C#N)cc2)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(OCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
122 mg (1.09 mmol) of potassium tert-butoxide are suspended in 2 ml of dry 1,2-dimethoxyethane. 229 mg (1.09 mmol) of the compound from Example 100A and 100 mg (0.22 mmol) of the compound from Example 98A are then added successively. The reaction mixture is stirred at 60° C. for 2 h and, after cooling, at RT for a further 10 h. 5 ml of water are then added to the mixture. The precipitate formed is filtered off with suction and washed once with about 2 ml of cold water. This is followed by purification by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:6].C(Cl)(=O)C(Cl)=O.[C:31](O)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([C:5](=[O:6])[C:4]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:2]([Br:1])[CH:3]=1)[CH3:20])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)O
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a cooled solution (0° C.) of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid (1.07 g, 2.60 mmol) in anhydrous DCM (10 mL), oxalyl chloride (0.34 mL, 3.90 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo and redissolved in anhydrous dichloromethane (5 mL). A solution of t-butanol (960 mg, 13 mmol) in anhydrous DCM (5 mL) was added and the mixture was stirred at room temperature overnight. After dilution with DCM, the mixture was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography (EtOAc/Hexanes: 1/4 with gradient up to EtOAc/Hexanes 1/3) afforded 1.1 g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid tert-butyl ester as a colorless oil. MS [M+H]+ (fragment):411.7 (f; tR=3.10 min, (method 1)
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>[Cl-].C[N+](C)(C)C>[Cl:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: Clc1nc2cc(I)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
Heat a solution of 5-iodo-1,3-dihydro-benzimidazol-2-one (6.50 g, 25.0 mmol; Feitelson et al. (1952) J. Chem. Soc. 2389) and tetramethylammonium chloride (1.37 g, 12.5 mmol) to 100° C. in POCl3 (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-iodo-1H-benzimidazole as a gray solid. B. 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (52 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (86 mg, 36%). 1H NMR (400 MHz, CDCl3) δ Shows rotomers 7.19-7.13 (2d, 2H), 6.91-6.88 (d, 2H), 4.05-4.02 (m, 2H), 3.85-3.80 (m, 2H), 3.56-3.45 (m, 4H), 2.67-2.65 (m, 2H), 2.60-2.56 (m, 4H), 2.32-1.96 (several multiplets, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of 3,5-dibromo-N-cyclopropyl-4-methylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow-orange oil.