Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:15])[CH:7]=[CH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:4].C(N(CC)CC)C.Cl>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH2:3]([O:5][C:6](=[O:15])/[C:7](/[Br:1])=[CH:8]/[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(Br)=C/C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
Add a solution of bromine (43.5 mL, 848 mmol) in carbon tetrachloride (500 mL) to a solution of 3-cyclohexyl-acrylic acid ethyl ester (154.5 g, 848 mmol) in dichloromethane cooled to −10° C. such that the temperature does not exceed 0° C. Stir the reaction mixture for 2 h at −10° C., and then add triethylamine (143 mL, 1.02 mol), again such that the temperature does not exceed 0° C. Allow the stirred reaction mixture to warm to r.t. overnight. Then dilute it with dichloromethane (500 mL), cool the resulting mixture to 0° C., and adjust the pH to a value of less than 2 by the careful addition of 1 N aqueous hydrochloric acid. Separate the resulting two layers, and extract the aqueous phase with dichloromethane (1 L). Combine the extract and the first organic layer, dry them over magnesium sulfate, and concentrate them under vacuum to afford a yellow oil. Apply a solution of this oil in dichloromethane to a silica gel column, and elute with a 1:1 mixture of dichloromethane and cyclohexane to afford the title compound as a yellow oil (103.5 g). MS (m/e): 262 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]2([CH2:17][CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)[O:3]1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[C:7]1([N:6]2[CH2:5][C:4]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[O:3][C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCCC2(C1)CN(c1ccccc1)C(=O)O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1OC2(CCCNC2)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.1 %

Procedure:
To a solution of the above-mentioned crude benzyl 2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate (2.0 g) in ethyl acetate (50 mL) was added 20% palladium hydroxide-carbon (200 mg), and the mixture was stirred at room temperature for 20 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the object product (800 mg, 53%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)(O)[O-].[K+].F[C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.O>CS(C)=O.C(OCC)(=O)C>[CH2:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CCCCCCOc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 10 h

Procedure:
To a suspension of 1-(4-hexyloxyphenyl)piperazine dihydrochloride (0.914 g) and potassium bicarbonate (0.564 g) in dimethylsulfoxide (5 ml) was added ethyl p-fluorobenzoate (0.2 ml) and stirred for 10 hours at 150° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (0.347 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) in N,N-dimethylacetamide (4.0 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (51 mg, 0.321 mmol) in N,N-dimethylacetamide (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallized from methanol/ethyl acetate to give the title compound (88.8 mg, 65%) as pale-yellow crystals. melting point 237° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH:19]([O:21][CH3:22])C.[H-].[Na+].[Br-]>CN(C=O)C.CC(=O)OCC>[CH3:22][O:21][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=1
Reactant: COC(C)CBr
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 700 mg) and 1-bromo-2-methoxypropane (490 mg) were dissolved in DMF (10 ml), and sodium hydride (77 mg) was added. After stirring at RT for 2 h, further bromide (100 μl) was added and the mixture was heated to 50° C. for 6 h. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 670 mg of the title compound were obtained. LC-MS rt: 1.71 min [M+H]+: 335.1 (met. a)
Reaction SMILES: Cl[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8].[NH:23]1[CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:2]2[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=2)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8])[CH2:25][CH2:24]1
Reactant: COC(=O)CCNC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CN1
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cc(N2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 83.7 %

Procedure:
A stirred solution of the above amide (315 mg, 0.95 mmol) in CH2Cl2 (35 mL) was treated with aziridine (197 μL, 3.81 mmol) at room temperature for 8 h. The mixture was partitioned between more CH2Cl2 and water, and the organic layer was dried and concentrated under reduced pressure. The residue was dissolved in EtOAc and filtered through a short column of silica gel to give 8 (269 mg, 84%): mp (CH2Cl2/iPr2O) 137° C.; 1H NMR [(CD3)2SO] δ8.86 (t, J=5.6 Hz, 1 H, NH), 8.66 (s, 1H, H-3), 7.40 (s, 1H, H-6), 3.63 (s, 3H, Me), 3.51-3.43 (m, 2H, NHCH2), 2.61 (t, J=6 8 Hz, 2H, CH2CO), 2 48 (s, 4H, aziridine-H). Anal. Calcd for C13H14N4O7: C, 46.15;H, 4 17; N, 16 57. Found: C, 45.89,H, 3.89; N, 16.45%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1>[Pd].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:11]=2[CH:12]=1
Reactant: CN1CCC2(CC1)COc1ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CN1CCC2(CC1)COc1ccc(N)cc12
Yield: 59.6 %

Procedure:
2,3-Dihydro-1'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D4, 0.98 g, 4.0 mmol) was hydrogenated over 10% palladium on charcoal (0.18 g) in ethanol (50 ml) for 6 h. Catalyst was filtered off onto kieselguhr, and the filtrated was evaporated and chromatographed on silica gel, eluting with 0-25% methanol/chloroform (gradient), to give the title compound (0.52 g, 60%) as a cream solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].OC1C2C(=CC(OC)=CC=2)N=CC=1C(OCC)=O.C(Cl)(=O)C(Cl)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CN(C=O)C>[OH:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Agent: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Temperature: 65 °C
Yield: 92 %

Procedure:
Ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. To a solution of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (2.72 g, 11.0 mmol) in chloroform (100 mL) was added oxalyl chloride (2.93 mL, 33.0 mmol) followed by 5 drops of DMF. The reaction was heated at 65° C. for 2.5 h before cooling to ambient temperature. The reaction mixture was poured into saturated NaHCO3 (aq.) solution and the organics were extracted with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (2.69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.33 (d, J=9.4 Hz, 1H), 7.58 (br. s., 1H), 7.37 (d, J=9.0 Hz, 1H), 4.48 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=266.2.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1.CO>S(=O)(=O)(O)O>[CH:9]1([C:13]2[C:22]([I:1])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(C2CCC2)cc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)c(C2CCC2)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portion-wise to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound 6.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at RT for 2 hours, upon where the mixture turned very thick. The mixture was again cooled to 0° C. and MeOH (30 mL) was slowly and carefully added. The mixture was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was poured onto ice water (100 mL). The mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, then aqueous 1M NaHCO3 (note-significant gas evolution), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield the title compound as a light yellow oil (4.17 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H), 1.82-1.79 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C2C(=CC=CC=2)C=CN1[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#N.C(N1CCC(=O)CC1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:14][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2nccc3ccccc23)CCN(Cc2ccccc2)CC1
Reactant: N#CC1c2ccccc2C=CN1C(=O)c1ccccc1
Agent: O=C1CCN(Cc2ccccc2)CC1
Product: O=C(OC1(c2nccc3ccccc23)CCN(Cc2ccccc2)CC1)c1ccccc1

Procedure:
A solution of 318 g. of 1-benzyl-4-(1-isoquinolyl)-piperidin-4-ol, obtainable by reacting 1-cyano-2-benzoyl-1,2-dihydroisoquinoline with 1-benzylpiperidin-4-one to give 1-benzyl-4-benzoyloxy-4-(1-isoquinolyl)-piperidine, which is subsequently hydrolyzed in 5 l. of methanol, is hydrogenated on 60 g. of 5% Pd-on-charcoal at 20° under 1 atmosphere of hydrogen. The mixture is filtered and the filtrate is evaporated to give 4-(1-isoquinolyl)-piperidin-4-ol, m.p. 138°-140°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1C(C)Oc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A mixture of methyl 3-methyl-4-(1-phenoxyethyl)benzoate (0.12 g, 0.44 mmol), lithium hydroxide monohydrate (285 mg, 6.8 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-4-(1-phenoxyethyl)benzoic acid (95 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2s1
Temperature: 85 °C

Procedure:
To a solution of 96 mg (0.25 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 5 ml acetonitrile was added 120 mg potassium carbonate and 0.3 ml (2-bromoethoxy)-tert-butyldimethylsilane. The reaction mixture was heated at reflux for 90 min and at 85° C. for 2 h and poured into 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 4:1 and then 9:1). [2-({5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzo[b]thiophene-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (40) (63 mg, 0.116 mmol) was obtained as a colorless solid.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][CH:28]([OH:30])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:26][C:21]1[CH:20]=[C:19]([S:18][C:12]2[N:11]([CH2:27][CH:28]([OH:30])[CH3:29])[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: CC(O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(O)Cn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 84.5 %

Procedure:
In 55 ml of concentrated hydrochloric acid was dissolved 13.4 g (28.7 mmol) of the alcohol (140a), and after the mixture was stirred with heating at 110° C. for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The mixture was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride-ethyl acetate=9:1), the oil was treated with ether and crystallized to provide 9.1 g (yield 84%) of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-1-(2-hydroxypropyl)-4-isopropyl-1H-imidazole (141a). mp 159-161° C.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:49])([CH3:48])[C:11]([O:13][C:14]1[CH:15]=[C:16]([CH2:35][C@H:36]([NH:40]C(OC(C)(C)C)=O)[C:37]([OH:39])=[O:38])[CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:34])[C:22]([CH3:33])([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56]([OH:59])(=[O:58])=[O:57])=[CH:52][CH:51]=1>>[S:56]([C:53]1[CH:54]=[CH:55][C:50]([CH3:60])=[CH:51][CH:52]=1)([OH:59])(=[O:58])=[O:57].[NH2:40][C@@H:36]([CH2:35][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21](=[O:34])[C:22]([CH3:23])([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:33])=[C:14]([O:13][C:11](=[O:12])[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:49])[CH3:48])[CH:15]=1)[C:37]([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)C(C)(C)OC(=O)c2ccccc2)c(OC(=O)C(C)(C)OC(=O)c2ccccc2)c1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(OC(=O)c1ccccc1)C(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1OC(=O)C(C)(C)OC(=O)c1ccccc1

Procedure:
(Method 3) a method in which after (2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid is subjected to a deprotection reaction using p-toluenesulfonic acid, a solvate of (2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid tosylate is produced without performing an isolation operation, followed by drying by heating under reduced pressure, whereby a type B crystal is produced; and
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][CH2:19][C@:10]2([O:14][CH2:13][C:12]([Sn](C)(C)C)=[CH:11]2)[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].Br[C:31]1[CH:32]=[C:33]([O:46][CH3:47])[CH:34]=[CH:35][C:36]=1[N:37]1[C:41]([C:42]([F:45])([F:44])[F:43])=[N:40][N:39]=[N:38]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][CH2:19][C@:10]2([O:14][CH2:13][C:12]([C:31]3[CH:32]=[C:33]([O:46][CH3:47])[CH:34]=[CH:35][C:36]=3[N:37]3[C:41]([C:42]([F:43])([F:44])[F:45])=[N:40][N:39]=[N:38]3)=[CH:11]2)[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(C=C([Sn](C)(C)C)CO2)[C@@H]1c1ccccc1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)c(Br)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nnnc2C(F)(F)F)c(C2=C[C@@]3(CCCN(C(=O)OC(C)(C)C)[C@H]3c3ccccc3)OC2)c1
Temperature: 110 °C
Yield: 89.7 %

Procedure:
A mixture of (5R,6S)-7-(tert-butoxycarbonyl)-6-phenyl-3-(trimethylstannyl)-7-aza-1-oxa-spiro[4.5]dec-3-ene (0.5 g, 1 mmol; Desc.6), lithium chloride (0.266 g, 6 mmol) and 3-bromo-4-(5-(trifluoromethyl)-tetrazol-1-yl)anisole (0.404 g, 1.2 mmol; Desc. 7c) in toluene (15 ml) was degassed and purged with nitrogen before addition of tetrakis(triphenylphosphine)palladium(0) (0.06 g). The mixture was degassed thoroughly, and the solution was heated to 110° C. for 19 hours. The solvent was evaporated in vacuo. The residue was dry loaded onto silica from methanol, and purified by chromatography on silica eluting with 10-20% ethyl acetate in hexane, to afford the title compound as a yellow oil (500 mg, 90%) MS (CI+) m/z 558 (M+H, 60%). 1H NMR (250 MHz, CDCl3) δ 1.34 (9H, s), 1.50 (1H, m), 1.55 (1H, m), 1.67 (1H, m), 1.87 (1H, m), 3.08 (1H, m), 3.88 (3H, s), 4.02 (1H, m), 4.30 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.46 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.92 (1H, s), 5.30 (1H, t, J 0.9 Hz), 6.68 (1H, d, J 2.8 Hz), 6.98 (1H, dd, J 2.8 Hz, J 8.8 Hz), 7.25 (6H, m).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(C2OC=NC=2)=CC=1>>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:2]=[CH:3][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Agent: FC(F)(F)c1ccc(-c2cnco2)cc1
Product: FC(F)(F)c1ccc(-c2cncc3c2CCC3)cc1
Yield: 32 %

Procedure:
In analogy to the procedure described for the preparation of 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindine (intermediate A-14 [B], batch approach), replacing 5-(3-fluoro-4-(trifluoromethyl)phenyl)-oxazole with 5-(4-trifluoromethyl-phenyl)-oxazole (CAS[87150-14-9]). The title compound was obtained as a light brown oil in 32% yield. MS: 264.1 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1[CH2:41][CH:40](C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)[CH2:39]1.C(NC(=O)CCl)(C)C>>[CH:40]([NH:30][C:28](=[O:29])[CH2:27][N:25]1[CH2:24][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:26]1)([CH3:41])[CH3:39]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: CC(C)NC(=O)CCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and N-isopropyl-2-chloroacetamide gave 470 isolated as a yellow solid (91 mg, 26%). LCMS: RT=3.31 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.05 (1H, s), 7.40 (1H, d, J=8.06 Hz), 7.17 (1H, dd, J=8.24, 1.83 Hz), 6.99 (1H, d, J=1.78 Hz), 5.83-5.73 (1H, m), 4.35-4.29 (2H, m), 3.86-3.80 (1H, m), 3.69-3.58 (3H, m), 3.41-3.35 (2H, m), 3.18 (2H, d, J=6.73 Hz), 3.00 (2H, s), 1.50 (6H, d, J=6.59 Hz), 1.03 (6H, d, J=6.59 Hz)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC#N>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
7-Cyano-1,2,3,4-tetrahydroisoquinoline (7 g; 44.25 mmol; 1 eq.) and K2CO3 (7.34 g; 53.1 mmol; 1.2 eq) were suspended in CH3CN (280 mL). tert-Butyl 3-bromopropionate (7.77 mL; 46.46 mmol; 1.05 eq.) was added. The reaction mixture was heated to 70° C. for 24 hours. As the reaction was not complete, tert-butyl 3-bromopropionate (3.70 mL; 22.12 mmol; 0.50 eq.) and K2CO3 (3.06 g; 22.12 mmol; 0.5 eq) were added and the mixture was stirred at 70° C. for additional 48 hours. Solvents were removed under vacuum and the solid residue was partitioned between NaHCO3 sat (100 mL) and EtOAc (200 mL). The organic layer was then washed with brine and dried over magnesium to give the title compound as a yellow oil (11.9 g; 93.9%). It was used in the next step without further purification. 1H NMR: (DMSO-d6, 400 MHz) δ 7.57-7.54 (m, 2H), 7.32-7.29 (m, 1H), 3.59 (s, 2H), 2.87-2.83 (t, J=5.94 Hz, 2H), 2.74-2.66 (m, 4H), 2.46-2.42 (t, J=7.01 Hz, 2H), 1.39 (s, 9H). HPLC/MS: 287.1 (M+H)+. HPLC (Method A) Rt 2.37 min (Purity: 96.4%).