Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.[I+].[Cu+].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>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#C[Si](C)(C)C)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.6 mmol) in toluene (20 mL) was added NEt3 (1 mL), copper (I) iodine (50 mg, 10%), tetrakis(triphenylphosphine)palladium (0) (305 mg, 10%) and (trimethylsilyl)acetylene (0.45 mL, 3.18 mmol). The reaction mixture was stirred and heated at 100° C. for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtoAc, 5:1 to 2:1) to afford an oil (770 mg, 74%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H), 4.10 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.37 (d, 1H, J=3.0 Hz), 8.05 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:19][C:20]1[S:24][C:23]([C:25](OCC)=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:25]([C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:26])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 68 %

Procedure:
A 0.25M THF solution of tert-butyl acetate (2.90 g, 25 mmol) is added dropwise to a cold (−78° C.) solution of potassium bis(trimethylsilyl)amide (100 ml of a 0.5M toluene solution) and ethyl 5-chlorothiophene-2-carboxylate (Lancaster)(4.77 g, 25 mmol) in 50 ml of THF. The reaction is allowed to warm to 0° C. over one hour. After stirring an additional hour at 0° C., the reaction is poured into 100 ml of a 1M HCl solution. The organic layer is extracted with brine and evaporated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% ethyl acetate/hexane to provide the product (4.54 g, 17 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7,53 (d, 1H), 6.98 (d, 1H), 3.78 (3, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.I[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 533.9 mg (2.6389 mmol) of 4,4-dimethyl-6-ethynylthiochroman (from Example 4) in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.7 ml of 1.6M (2.72 mmol) n-butyl lithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 15 minutes, cooled again to 0° C. and then treated with a solution of 410 mg (3.005 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter, the solution was stirred at 0° C. for 45 minutes, then at room temperature for 20 minutes. A solution of 724.4 mg (2.6243 mmol) of ethyl 4-iodobenzoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 520 mg (0.45 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 20 minutes, then treated by double ended needle with the solution of the alkynyl zinc chloride prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with ice and 30 ml 3N hydrogen chloride. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a colorless oil. PMR (CDCl3) :δ 1.36 (6H), 1.42 (3H, t, J~7 Hz), 1.93-1.99 (2H, m), 3.03-3.08 (2H, m), 4.40 (2H, q, J~7 Hz), 7.09 (1H, d, J~8.4 Hz), 7.22 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.56 (1H, d, J~2.11 Hz), 7.59 (2H, d, J~7.8 Hz), 8.04 (2H, d, J~7.8 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)[O:11][CH:10]([C:19]([O:21]CCCC)=[O:20])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)[O:11][CH:10]([C:19]([OH:21])=[O:20])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)C1CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(C(=O)O)CC2
Temperature: 70 °C
Yield: 98 %

Procedure:
To a toluene solution (183.0 g, 0.2 mol) of 6,8-di-t-butyl -2-butoxycarbonylchroman obtained in Example 2 were added 10% aqueous sodium hydroxide solution (120.0 g, 0.3 mol) and methanol (120 g), and the mixture was stirred while heating at 70° C. for 2 h. Toluene was added to the reaction mixture and the mixture was stirred and allowed to stand, and methanol and the like were removed from the aqueous layer. After the removal, aqueous sulfuric acid solution was added to the aqueous layer, and the mixture was extracted with toluene. The extract was concentrated under reduced pressure. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. As a result, 6,8-di-t-butyl-2-hydroxycarbonylchroman was obtained in a yield of 98% [net 56.92 g, 0.196 mol]. The 1H-NMR data of the obtained 6,8-di-t-butyl-2-hydroxycarbonylchroman are shown below.
Reaction SMILES: [ClH:1].O[CH:3]([CH3:17])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:20].[ClH:1].[Cl:20][CH:3]([CH3:17])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CC(O)CN1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
1-(2-Hydroxypropyl)-4-phenylpiperazine hydrochloride (155 g.) was suspended in 1200 ml. dry chloroform and 87.5 ml. thionyl chloride added dropwise. The mixture was refluxed 21/2 hrs, and cooled overnight at room temperature. The solid was filtered, washed with chloroform, them with ether, and dried to give 175 g., m. 216-18° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.Cl.[CH3:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][OH:18])[NH2:16].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:19])[CH:15]([NH:16][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH2:17][OH:18]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol), serine methylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9 mmol) in DMF (100 ml) was added N-methylmorpholine (NMM) (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3×250 ml) followed by brine. The organic extract was dried over Na2SO4 (anhydrous) and then concentrated in vacuo giving 2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 93%) of a pale yellow solid. 1H NMR (CDCl3) d (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, 1 H), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, 1 H).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][N:25]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1>ClCCl>[ClH:1].[CH3:26][C:23]1[O:22][C:21]([C:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=2)=[N:25][CH:24]=1
Reactant: Cc1cnc(C2=CCN(Cc3ccccc3)CC2)o1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cc1cnc(C2=CCNCC2)o1
Product: Cl
Reaction time: 2 h
Yield: 84.5 %

Procedure:
20 g 1-chloroethyl chloroformate was added to 24 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-1,2,3,6-tetrahydro-pyridine in 200 mL anhydrous dichlormethane at 0° C. under nitrogen atmosphere. After 2 h, the solution was concentrated and 200 mL anhydrous methanol was added. The mixture was heated at reflux for 4 h and concentrated. The resulting crude product was re-crystallized from dichlormethane to give 16 g of the desired product.
Reaction SMILES: [CH3:1][C:2]([OH:40])([CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[S:21][C:17]=3[CH:16]=2)=[CH:11][CH2:10]1)(=[O:8])=[O:7])[CH3:3].[O:41]=[C:42]([O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:43][CH2:44][C:45](O)=[O:46].N1(C2C=CN=CC=2)CCCC1.CC(C)N=C=NC(C)C>C(Cl)Cl>[C:45]([O:40][C:2]([CH3:3])([CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29]5[N:30]=[CH:31][C:32]([CH2:35][CH2:36][CH3:37])=[CH:33][N:34]=5)[CH2:25][CH2:24]4)[S:21][C:17]=3[CH:16]=2)=[CH:11][CH2:10]1)(=[O:7])=[O:8])[CH3:1])(=[O:46])[CH2:44][CH2:43][C:42]([O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])=[O:41]
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)O
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)O)CC5)cc4s3)CC2)nc1
Agent: CC(C)N=C=NC(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OC(=O)CCC(=O)OCC[Si](C)(C)C)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-ol (250 mg, 0.427 mmol), 4-oxo-4-(2-(trimethylsilyl)ethoxy)butanoic acid (compound 39B, 466 mg, 2.13 mmol), and 4-(pyrrolidin-1-yl)pyridine (95 mg, 0.640 mmol) in CH2Cl2 (8.6 mL) at rt was added DIC (332 μl 2.134 mmol). The mixture was heated to reflux for 5 h. The mixture was cooled to rt, diluted with CH2Cl2 (4 mL), and washed sequentially with cold aq. HCl (1 N, 3 mL), cold aq. NaHCO3 (10%, 2 mL), water (2 mL), and brine (2 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 45% EtOAc) to afford Compound 39B as a light yellow solid (287 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 2H), 7.65-7.54 (m, 2H), 7.36 (dd, J=8.4, 1.9 Hz, 1H), 6.10-5.97 (m, 1H), 5.42 (tt, J=7.8, 3.8 Hz, 1H), 4.26-4.09 (m, 4H), 4.01 (d, J=3.0 Hz, 2H), 3.70-3.61 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.11-3.01 (m, 2H), 2.69-2.61 (m, 2H), 2.56-2.45 (m, 4H), 2.42-2.33 (m, 2H), 2.28-2.18 (m, 2H), 2.15 (m, 2H), 1.91 (dtd, J=12.4, 8.2, 3.9 Hz, 2H), 1.55 (dd, J=15.0, 7.4 Hz, 2H), 1.45 (s, 6H), 0.92 (dd, J=13.0, 5.7 Hz, 4H), 0.02 (m, 2H), 0.00 (s, 9H). LCMS (m/z)=787 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:13]=1>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([CH:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[N:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][CH:14]=3)=[O:19])[CH2:25][CH2:24]2)=[O:34])=[CH:32][CH:31]=1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: CC(C)[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 25.7 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (408 mg) described in Preparation Example 190 and by the reaction and treatment in the same manner as in Example 4, the title compound (126 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].I[CH:13]([CH3:15])[CH3:14].[CH3:16][C:17]1([CH3:30])[C@@H:19]2[CH2:20][C:21]3[C:25]([C@H:18]12)=[C:24]([CH3:26])[S:23][C:22]=3[C:27]([OH:29])=O>>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:9][CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:27]([C:22]1[S:23][C:24]([CH3:26])=[C:25]2[C:21]=1[CH2:20][C@H:19]1[C:17]([CH3:16])([CH3:30])[C@H:18]12)=[O:29]
Reactant: CC(C)I
Reactant: COc1cc(O)ccc1CN
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Product: COc1cc(OC(C)C)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C

Procedure:
(1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-isopropoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 2-iodopropane and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: tR=1.12 min, [M+1]+=400.17.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]([CH2:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([CH:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH3:21]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)c2cc(OC)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CCNc2cc(OC)ccc21
Yield: 93.8 %

Procedure:
In a oven dried 250 mL r.b. flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-1-t-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline (34.0 mg, 117 μmol) in dry CH2Cl2 (1 mL). To the stirred solution was added TFA (1.2 mL) at rt and was allowed to react for 2 h. The dark red solution was quenched with sat NaHCO3 solution (10 mL), extracted with CH2Cl2 (3×25 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 21 mg (95%) of the desired amine as a clear light yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline: Rf =0.1 (hexanes/EtOAc, 3: 1); 1H NMR (400 MHz, CDCl3) 6.92 (d, J=8.5, 1H), 6.21 (dd, J=2.5, 8.2, 1H), 6.03 (d, J=2.5, 1H), 3.73 (s, 3H), 3.27 (m, 2H), 2.59 (m, 1H), 1.86 (m, 1H), 1.75 (m, 2H), 1.48 (m, 1H), 0.968 (t, J=7.4, 3H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([Br:30])[CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[CH:26]=[CH:25]3)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[Br:30][C:22]1[CH:23]=[C:24]2[C:28](=[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]3=[O:31])[CH:21]=1)[N:27]([CH3:29])[CH:26]=[CH:25]2
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(5-Bromo-1-methyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (10 mg, 0.02 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (1 mg, 0.04 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 471.17 (M+H+).
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[N:2]1.[C:11]([O:15][C:16]([CH2:18][O:19][NH2:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1.O>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([OH:9])=[O:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1cnsn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cnsn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (1,2,5-thiadiazol-3-yl)glyoxylic acid (6 g) in tetrahydrofuran (30 ml) and water (30 ml) was added tert-butoxycarbonylmethoxyamine (8.37 g) at ambient temperature. The mixture was adjusted to pH 4.5-5.0 with 4N aqueous sodium hydroxide and stirred at ambient temperature for 4 hours. The mixture was adjusted to pH 7.5 with 4N aqueous sodium hydroxide and washed with ethyl acetate (100 ml×2). The aqueous solution was acidified to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml×2). The organic layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. The solution was evaporated in vacuo to give 2-tert-butoxycarbonylmethoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn and anti mixture) (10.02 g).
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Ca+2].[Cl-]>ClCCCl.CCCCCC>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:1]=[O:2])=[CH:21][C:20]=1[CH2:25][CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(Cl)Cl
Reactant: CCc1ccccc1OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCCCCC
Product: CCc1cc(C=O)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 25 g of 1,2-dichloroethane was dissolved 3.25 g (28 mmol) of dichloromethyl methyl ether, and the solution was chilled with ice-water. Here was added dropwise 7.36 g (28 mmol) of anhydrous tin (IV) chloride, and the mixture was stirred for 10 minutes. Here was added dropwise 5.00 g (23.55 mmol) of 1-benzyloxy-2-ethylbenzene obtained in Step 2 dissolved in 1,2-dichloroethane, and the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture, aqueous solution of calcium chloride was added dropwise at 20° C. or below, 15 g of hexane was added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane=1:10, SiO2) to yield the desired product, 4-benzyloxy-3-ethylbenzaldehyde, as yellow liquid (3.17 g, Yield: 56%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:31]3[CH2:32][CH2:33][O:28][CH2:29][CH:30]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.I([O-])(=O)(=O)=[O:31].[Na+]>O.C(OCC)(=O)C.C(OCC)(=O)C.O.[Ru](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][C:20]3=[O:31])[C:7]=2[CH:29]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Temperature: 25 °C
Reaction time: 53 h
Yield: 24.5 %

Procedure:
A mixture of tert-butyl {1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 47, 1.39 g, 3.4 mmol) in water/ethyl acetate (40 mL, 4:1) was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV) oxide hydrate (50 mg, 0.34 mmol) at room temperature. After 53 hours, the reaction was diluted with ethyl acetate, the aqueous phase was extracted with ethyl acetate (6×25 mL), and the combined organic layers were mixed with 2-propanol (20 mL) and stirred for 2 hours at room temperature. The reaction mixture was then filtered through celite, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 350 mg (25%) of the product as a colorless solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:38](=[O:40])[CH3:39])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(C)=O)CC4)nc12
Yield: 74 %

Procedure:
To a suspension of 0.037 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.007 ml acetylchloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.028 g (74%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone as yellow solid; M.p.: 195–197° C.; MS (ISP): m/e=428 (M+H+).