Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[Cl:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Clc1cccc([Mg]Br)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (2.0 g) in tetrahydrofuran (100 mL), 3-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 2.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc2nc(-c3ccc(OCCCCl)cc3)cn2c1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C

Procedure:
The product of Step C (8.6 g) and dibutylamine (9 mL) were heated at reflux temperature for 8 hours. The reaction was cooled to ambient temperature and evaporated in vacuo. The residue was purified via silica gel chromatography (dichloromethane/acetone) to give the title compound which was converted to a hydrochloride salt upon addition of concentrated hydrochloric acid. The salt was recrystallized (methanol/acetone/ether) to give 5.66 g of product. (m.p. 188-191° C).
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17]>O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH3:17]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1cc(C=C2COc3cc(O)ccc3C2=O)ccc1OC
Reaction time: 22.5 h
Yield: 20.6 %

Procedure:
After a saturated hydrogen chloride-methanol solution 15 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-ethoxy-4-methoxybenzaldehyde 1.30 g, the mixture was srtirred for 22.5 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 30 ml of 55° C., and the mixture was filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.415 g.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:11])[CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[N:13]#[C:14][NH2:15]>>[ClH:1].[CH2:6]([C:5]1[N:11]=[C:14]([NH2:15])[NH:13][CH:4]=1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCc1c[nH]c(N)n1
Yield: 90 %

Procedure:
2-Amino-hept-6-ynoic acid methyl ester hydrochloride (2.00 g, 10.4 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (1.75 g, 90%) as a pale oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CDCl3) δ 6.68 (bs, 2H), δ 6.24 (s, 1H), δ 2.51 (t, 2H), δ 2.17 (t, 1H), δ 1.95 (s, 1H), δ 1.74 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 148.3, 132.7, 111.6, 84.4, 69.1, 28.0, 26.0, 18.2 ppm; HRMS (ESI) calcd for C10H16N3(M+) 150.1026, found 150.1029.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 49.3 %

Procedure:
A solution of 15.18 g (0.0529 mole) of 4-[bis(4-flurophenyl)methylene]piperidine and 10,89 g (0.0617 mole) of benzenesulfonyl chloride in 350 ml of pyridine was stirred at room temperature for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sulfuric acid. The methylene chloride solution was extracted with dilute sodium hydroxide, and the methylene chloride solution was dried over sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in 200 ml of methanol. A precipitate was collected. This was recrystallized from methylene chloride - methanol to give 11.14 g (49.3%) of the title compound as a white solid: mp 180-184° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH2:18][CH:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:20])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: CC=CC(=O)c1cc(-c2ccccc2)no1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC(=O)c1cc(-c2ccccc2)no1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyrrolidine (5 ml) was added to 1.1 g (5.2mmol) of 3-phenyl-5-(2-butenoyl)isoxazole prepared above in the procedure (1). The resulting mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, so that a product formed was extracted in an organic layer. The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated, whereby 3-phenyl-5-{3-(1-pyrrolidinyl)butyryl}isoxazole was obtained as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:29])[CH3:28])[N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:29])[CH3:28])[N:13]=2)=[CH:8][CH:7]=1)=[O:4])[CH3:31]
Reactant: CCNCC
Reactant: CC(=O)N1N=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2CC1C)OCO3
Product: CCN(CC)CC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1

Procedure:
It was prepared from 1-(4-chloroacetylaminophenyl)-3-acetyl-4-methyl -7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and diethylamine by using the process described in Example 102, m.p. 175°-176° C.
Reaction SMILES: [Br:1]C1C=CN=C2C(N3CCNCC3)C3C=CC(Cl)=CC=3CCC=12.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:38]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[CH2:31][CH2:30][C:29]=2[CH:45]=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][C:53]([OH:55])=O)[CH:47]=1.N1C=CC(CC(O)=O)=CC=1>>[Br:1][C:36]1[CH:37]=[C:32]2[CH2:31][CH2:30][C:29]3[CH:45]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=3[CH:38]([N:39]3[CH2:40][CH2:41][N:42]([C:53](=[O:55])[CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)[CH2:43][CH2:44]3)[C:33]2=[N:34][CH:35]=1
Reactant: Clc1ccc2c(c1)CCc1c(Br)ccnc1C2N1CCNCC1
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: O=C(O)Cc1ccncc1
Product: O=C(Cc1cccnc1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Yield: 95 %

Procedure:
By substituting in Example 75, 3-bromo-8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0.32 g, 0.81 mmoles) (Preparative Example 40) for 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid (0.117 g, 0.86 mmoles) for 4-pyridylacetic acid and using the method described in Example 75, one obtains the title compound (0.3942 g, 95%, MH+511).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.CCCCCC>C(O)C.[Pd]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCc2ccc(O)cc2O1

Procedure:
A solution of 7-hydroxycoumarin (5.0 g, 0.031 mol; Aldrich Chemical Company) in absolute ethanol (200 mL) was hydrogenated under pressure in a Parr apparatus over 10% Pd/C (Catalyst; 500 mg, 50% water; Kodak, Inc., Rochester, N.Y.) for 24 hours at 55° C. Thin layer chromatography (TLC; Silica gel: EtOAc/hexane: 1:1) showed completion of the reaction. The reaction mixture was then filtered over a bed of Celite (Rohm and Haas Co., Philadelphia, Pa.) and evaporated in vacuo to provide the crude product (4.5 g). A portion (2.5 g) of this material was recrystallized from toluene and dried under vacuum to provide 7-hydroxydihydrocoumarin. Yield: 1.83 g; melting point 133°-135.5° C.;
Reaction SMILES: [NH:1]([C:14](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2](C(O)=O)[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.[CH:31](=O)[CH2:32]C.[NH:35]([C:47]([O:49]C(C)(C)C)=O)[C@H:36]([C:44]([OH:46])=O)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CC(O)=O.C1(C)C=CC=CC=1.O>[CH2:37]([C@H:36]1[C:44](=[O:46])[N:1]([CH2:14][CH2:31][CH3:32])[C@@H:2]([CH2:3][C:4]([OH:5])=[O:10])[C:47](=[O:49])[NH:35]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCCN1C(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]1CC(=O)O

Procedure:
Hydroxymethyl PAM resin was coupled with FmocAsp(OtBu)-OH (Mukaiyama conditions) and reductively alkylated with propionaldehyde. BocPhe was coupled with HOAt/DIC and after Boc-deprotection the DKP formed in 1% HOAc/toluene (12 h). Yield: 45 mg (22%). 1H-NMR (400 MHz, CDCl3):δ=0.89 (t,J=7.3 Hz, 3 H), 1.45-1.49 (m,1 H), 1.65-1.69 (m, 1 H), 1.92 (dd, J=6.5, 16.7 Hz, 1 H), 2.10 (dd, J=3.6, 16.7 Hz, 1 H), 2.86-2.93 (m, 1 H), 3.11 (dd, J=3.6, 13.5 Hz, 1 H), 3.24 (dd, J=6.4, 13.5 Hz, 1 H), 3.59-3.67 (m, 1 H), 4.25 (m, 1 H), 4.36 (m, 1 H), 5.41 (broad s, 1 H), 7.16-7.18 (m, 2 H), 7.30-7.34 (m, 2 H), 7.50-7.54 (m, 1 H). 13 C-NMR (101 MHz, CDCl3):δ=11.1, 19.9, 36.9, 40.3, 46.6, 55.8, 56.5, 127.7, 128.9, 130.2, 134.9, 164.9, 168.3, 173.5. Anal. Calcd. for C16H20N2O4.1.5 H2O:C,57.99; H, 7.00; N, 8.45, found: C, 57.45; H,6.35; N, 8.91
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[F:24])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1ccccc1F
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4F)c3)csc12

Procedure:
3-[3-(2-Fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and 2-fluorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C:28](=O)[CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:28]2[CH2:27][C:26]3[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=3)[CH2:29]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1Cc2ccc(Cl)cc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1Cc2ccc(Cl)cc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 5-Chloro-indan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 24.3, 26.6, 26.7, 36.4, 39.3, 39.8, 40.0, 40.4, 56.0, 59.1, 59.2, 61.4, 67.3, 104.8, 125.1, 125.2, 125.9, 126.0, 126.9, 126.9, 131.2, 137.3, 140.1, 143.2, 143.6, 172.0; MS m/z 458.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:20]1[O:21][C:17]([CH3:16])=[CH:18][CH:19]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(CNCCCc2ccc3ccccc3c2Cl)o1
Yield: 89 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-methylfuran-2-carbaldehyde in 89% yield as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)nc2ccc(Br)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(O)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-2-hydroxyquinoline-4-carboxylic acid (9.0 g) was dissolved in dichloromethane and cooled to 0° C. 3-aminopyridine (1 eq), T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, 50% solution in ethyl acetate, 1.2 eq.), and DIPEA (diisopropylethylamine, 2.0 eq) were added. The solution was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature overnight. The solution was washed with water, sat. sodium chloride, dried, and concentrated. Purification by silica gel column chromatography provided 6-bromo-2-hydroxy-N-(pyridin-3-yl)quinoline-4-carboxamide (9.0 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Br:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Br)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2.36 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to a solution of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide, during which the reaction mixture was cooled with cold water. The resulting solution was stirred at room temperature for two hours and then poured into 800 ml water. The precipitate was collected, washed with water and dried under vacuum (P2O5) to give 3.7 g solid;
Reaction SMILES: [H-].[Na+].C([SiH2]OC(C)(C)C1NC(=O)CCC1)(C)(C)C.I[CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]#[C:21][CH3:20]
Reactant: COC(=O)CCCC#CCI
Agent: CC(C)(C)[SiH2]OC(C)(C)C1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCCCC(=O)OC
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 219 mg, 5.27 mmol) was added to a solution of 6-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-2-one (1.27 g, 5.21 mmol) in DMF (10 mL) at rt. After 1 h, methyl 7-iodohept-5-ynoate (1.52 g, 5.73 mmol) in DMF (2 mL) was added via cannula. After 18 h at rt, the reaction was quenched by the addition of aqueous HCl (0.5 M, 15 mL) and the mixture was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (3×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→40% EtOAc/CH2Cl2, gradient) afforded 1.04 g (53%) of 7-[2-tert-butyl-dimethyl-silanyloxymethyl)-6-oxo-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)(C(OCC=C)=O)[C:27]([O:29]CC=C)=[O:28])=[CH:20][CH:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)[C:27]([OH:29])=[O:28])=[CH:22][CH:23]=1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC(C)(C)C)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CC(CCc2ccc(C(=O)OC(C)(C)C)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
A solution of 0.79 ml (5.66 mmol) of triethylamine and 0.16 ml (4.29 mmol) of formic acid in 10 ml of dioxane is added to a solution of 920 mg (1.71 mmol) of diallyl {2-[4-(tert-butoxycarbonyl)phenyl]ethyl}[4-(methoxycarbonyl)benzyl]malonate, 31.5 mg (0.12 mmol) of triphenylphosphine and 7.7 mg (0.03 mmol) of palladium acetate in 10 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 497 mg (1.2 mmol, 61% yield) of a colourless solid are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH3:21][CH:20]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[CH3:22]
Reactant: CC(C)I
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cccc2c1CCCC2=O
Temperature: 80 °C

Procedure:
A mixture of 2.5 g of 5-hydroxy-1-tetralone, 30 ml of acetonitrile, 5 g of caesium carbonate and 3.87 ml of 2-iodopropane is heated for one hour at 80° C. and then evaporated to dryness. The residue is taken up in ethyl acetate and water. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 4.87 g of 5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of an orangey-coloured oil.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:34]=[CH:33][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3-]C#N.[Na+].CCOC(C)=O>C(O)(C(F)(F)F)=O.O>[CH:1]1([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:23])=[CH:33][CH:34]=3)(=[O:16])=[O:17])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(C3CCCC3)c3ccccc32)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
Add 4-(3-cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (0.152 g, 0.319 mmol) portionwise to a stirring mixture of NaCNBH3 (0.096 g, 1.52 mmol) in TFA at 0 to 5° C. under N2. Stir the mixture for 15 minutes at 0-5° C., allow to warm to ambient temperature and add an additional 0.096 g NaCNBH3. Stir the resulting yellow solution for 2 h at ambient temperature, dilute with H2O (13.0 mL) and stir overnight. Pour the reaction mixture is into EtOAc (100 mL). Separate the EtOAc, extract with H2O, 5% NaHCO3 and wash with brine. Separate the EtOAc, dry (MgSO4), filter and evaporate giving a glass. Chromatograph on the chromatotron eluting with EtOAc-hexane 3:7 to give 0.060 g of the title compound: Mass spectrum (m/e) (M+H) 479.1805; found 479.1788.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([CH2:27][O:28][C:29]2[C:33](/[CH:34]=[CH:35]/[C:36]3[N:37]=[C:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[S:39][C:40]=3[CH3:41])=[CH:32][N:31]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:30]=2)[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([CH2:27][O:28][C:29]2[C:33](/[CH:34]=[CH:35]/[C:36]3[N:37]=[C:38]([N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[S:39][C:40]=3[CH3:41])=[CH:32][N:31]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:30]=2)[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])[O:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCOCC5)sc4C)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCOCC3)sc2C)ccc1OCc1nc(-c2cccc(C(=O)O)c2)oc1C
Yield: 72.8 %

Procedure:
To a mixture of methyl 3-[4-({2-methoxy-4-[({4-[(E)-2-(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.35 g), tetrahydrofuran (50 mL) and methanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was heated under reflux for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether to give 3-[4-({2-methoxy-4-[({4-[(E)-2-(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy)methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as brown crystals (0.25 g, yield 71%). Recrystallization from acetone-hexane gave brown prism crystals. melting point: 215-217 (dec) ° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7]>C(O)(=O)C>[CH3:3][CH2:2][O:1][CH2:5][CH3:4].[C:6]([O-:9])(=[O:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: CCOCC
Temperature: 45 °C

Procedure:
The obtained catalyst was pulverized into 40-80 mesh. 20 g of the pulverized catalyst was placed in a slurry reactor, 100 g of tetrahydrofuran, 8 g of acetic anhydride and 1 g of acetic acid were added. The temperature of the reactor was raised to 45° C. and reacted for 90 minutes. After filtration and separation unreacted tetrahydrofuran by reduced distillation, polytetramethylene ether acetate was obtained. The properties of the resultant polymer are listed in Table 1.