Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[C@H:17]([C:31](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:32])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:54][C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[C:70][CH3:71])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH2:68]([O:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][C@H:55]([NH:54][C:31]([C@@H:17](/[CH:16]=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:32])[C:56]([O:58][CH3:59])=[O:57])=[CH:66][CH:65]=1)[C:69]#[C:70][CH3:71]
Reactant: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)N1C(=O)SC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCSCCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
tert-Butyl (E)-(2S,3S)-11-heptylsulfanyl-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804239; 68.3 mg, 0.0889 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (33.0 mg, 0.133 mmol) were dissolved in dichloromethane. The solvent was distilled off under reduced pressure. The resulting mixture was stirred at 50° C. for 5 days, cooled to room temperature, and then extracted by adding ethyl acetate and water. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure. The residue was purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.1) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804240; 50.9 mg, 80% yield)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:31]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([Cl:30])[CH:21]=1>>[Cl:30][C:22]1[CH:21]=[C:20]([C:19]2[N:18]=[C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])=[C:2]([CH3:1])[CH:7]=3)[O:10][N:31]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)cc1Cl

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.14 mg; 0.50 mmol) and Intermediate 34 (114.32 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as an off-white solid. LC/MS (Method B): 419.3 (M−H)−, 460.3 (M+ACN)+. HPLC (Method A) Rt 6.51 min (Purity: 99.8%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:20]
Reactant: CCOC(=O)CCBr
Reactant: Nc1cc2ccccc2cc1N
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNc1cc2ccccc2cc1N

Procedure:
A solution of 2,3-diaminonaphthalene (14.3 g, 90.4 mmol) and ethyl 3-bromopropionate (14 mL, 0.108 mol) in DMF (150 mL) was heated to 50° C. for 24 h. The reaction mixture was poured into water (600 mL) and the product was extracted into CH2Cl2 (2×200 mL). The combined organics were washed three times with water and dried over Na2SO4. The solvent was evaporated in vacuo and the resultant residue was purified by flash chromatography using 27% to 40% EtOAc in hexane as the eluant to give the product as a brown solid, 7.6 g (33%): MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.73 (t, 2H), 3.37-3.45 (m, 2H), 4.12 (q, 2H), 5.03 (br s, 2H), 5.09 (br t, 1H), 6.71 (s, 1H), 6.85 (s, 1H), 6.98-7.05 (m, 2H), 7.36-7.43 (m, 1H) and 7.47-7.53 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:18].[H][H]>O1CCOCC1.[Pd]>[ClH:18].[N:15]1[C:16]2[CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CN2CCc3cccnc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc2c(c1)CCNC2
Yield: 65 %

Procedure:
A methanolic solution (25 mL) of 7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridine (J. Het. Chem. 2001, 38, 535) (1.5 g, 6.69 mmol) was degassed with argon for 20 min followed by the addition of 4N HCl in dioxane (2 mL) and Pd/C (300 mg, 20 wt %) and stirred under 50 psi hydrogen pressure at room temperature for 24 h. After completion of the reaction the mixture was filtered on a short pad of celite and washed with methanol (4×25 mL). The filtrate was evaporated to dryness in vacuo and crystallized from methanol to afford the title compound as yellowish solid in 65% yield (calculated as 2HCl salt), 900 mg.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)#[N:2].[ClH:19].[H][H]>C(O)(=O)C.[Pt]=O>[ClH:19].[NH2:2][CH2:1][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:8][CH2:9]1
Reactant: N#CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reaction time: 6 h

Procedure:
14.1 g (0.05 mol) of N-(cyanomethyl)-4-(p-fluorobenzoyl)-piperidine are dissolved in 1.5 liters of glacial acetic acid and 30 ml of concentrated hydrochloric acid and hydrogenated together with 2 g of platinum oxide in a hydrogen atmosphere. After 6 hours, the theoretical amount of 2.25 liters of hydrogen is absorbed. The catalyst is then filtered off with suction and the filtrate is concentrated to approximately 30 ml in a water-jet vacuum. There is added to the resulting crystal mass 5 ml of isopropanol and 15 ml of ether and filtration with suction is carried out. After filtration with suction and drying, N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine hydrochloride is obtained which, after recrystallisation from methanol, melts at 265° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=[N+]([O-])O
Solvent: Clc1ccccc1Cl
Product: CC(C)n1c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
5-Chloro-1-isopropylbenzimidazol-2-one (4.0 g) was dissolved in o-dichlorobenzene (80 ml) and thereto was added dropwise 70% nitric acid (2.0 g). The mixture was stirred at 60° C. for 1 hour and left to stand for cooling. The precipitated crystal was separated by filtration and washed with diethyl ether and water to give 5-chloro-1-isopropyl-6-nitrobenzimidazol-2-one (4.1 g). A part of the obtained product was recrystallized from ethanol, which showed the following physical properties:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:25][CH3:26])=[CH:13][C:14]2[O:19][C:18](=[O:20])[C:17]3[CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:24]=1)(=O)=O.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][O:25][C:12]1[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:24][C:15]2[C:16]3[CH2:23][CH2:22][CH2:21][C:17]=3[C:18](=[O:20])[O:19][C:14]=2[CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCOS(C)(=O)=O)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 55 %

Procedure:
Method B (16 h at 80° C.); starting materials: 2,3-dihydro-8-[4-(methanesulfonyloxy)butyloxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 84) and 1-phenylpiperazine; yield 55%; fusion point 162°-165° C. (from ethanol). Fumarate: method E; yield 95%; fusion point 179°-183° C. (from acetone).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:30]([CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:31])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)C1CCOCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCOCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and tetrahydro-2H-pyran-4-carboxylic acid as a pale-yellow solid (63%). MS 430 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccsc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccsc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
A mixture of 4-(thiophen-3-ylmethoxy)-benzaldehyde (3.61 g, 16.5 mmol) described in Manufacturing Example 77-1-1, nitromethane (4.44 mL, 82.5 mmol), ammonium acetate (2.54 g, 33 mmol) and acetic acid (36 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.1 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1.C(O)C>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:21][NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:23][CH:22]=2)=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccnc2ccccc12
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NN=Cc1ccnc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of 7.86 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 8.53 gm (0.05 mole) of 4-chlorobenzhydrazide, 400 ml of ethanol and 100 ml of tetrahydrofuran is refluxed 2 hr. Thin layer chromatography of the reaction mixture establishes that the reaction is complete. The reaction mixture is concentrated to one-half the original volume and then cooled to room temperature. The solid which separates is collected, washed with ethanol and dried to give 13.18 gm (85%) of title compound, having a melting point of 232.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([N:16]([CH3:17])[CH3:15])=[O:14])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: COc1ncc(Br)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(Br)cc1/C=C/C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of (2E)-3-(5-bromo-2-methoxypyridin-3-yl)acrylic acid (1.00 g, 3.87 mmol) in DCM (10 mL) were added dimethylamine (2.0 M in THF, 5.80 mmol), DIEA (2.02 mL, 11.6 mmol) and TBTU (1.49 g, 4.65 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and then the aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (2E)-3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylacrylamide (1.05 g, 95%) as a white solid. LCMS (FA): Rt=1.68 min, m/z=285.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH2:26][C:27]([O:29]CC)=[O:28])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH2:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CSc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(SCC(=O)O)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of ethyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyridin-2-yl)sulfanyl]acetate obtained in Example 21 (390 mg), 1 M sodium hydroxide solution (12 mL), methanol (30 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 3 h. 1 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (336 mg, 99%) as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 180 °C
Yield: 18.2 %

Procedure:
A mixture of 1-chloro-5-fluoro-4-methyl-2-nitro-benzene (2 g, 10.55 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.32 g, 11.58 mmol), and iPr2NEt (3.8 mL) was heated for 2 hours at 180° C. by microwave heating. After cooling, the reaction mixture was diluted with CH2Cl2 and then filtered. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography (25% ethyl acetate in hexanes) to afford 4-(5-fluoro-4-methyl-2-nitro-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.68 g, 18%) as a brown solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])([C:24]#[N:25])[CH:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:11]2([C:24]#[N:25])[CH:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[C:15]([Cl:23])[CH:14]=2)=[C:27]([F:33])[CH:28]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 83 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (1.2 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as solid (1.1 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(Cl)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
A mixture of dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (100 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (79 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids collected by filtration. The crude solids were purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford (R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′ bicyclo[2.2.2]octan]-2-amine (62 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1 H) 7.93 (d, J=8.53 Hz, 1 H) 7.45 (d, J=8.28 Hz, 1 H) 3.92 (d, J=10.29 Hz, 1 H) 3.67 (d, J=10.29 Hz, 1 H) 3.00-3.14 (m, 2 H) 2.77-2.93 (m, 2 H) 2.69 (t, J=7.65 Hz, 2 H) 2.12 (br. s., 1 H) 1.95 (br. s., 1 H) 1.43-1.72 (m, 3 H). MS (LC/MS) R.T.=1.10; [M+H]+=350.10.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1>>[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(S(=O)(=O)Cl)cc1CC2
Reaction time: 0.33 h

Procedure:
Chlorosulfonic acid(25 ml, Aldrich), cooled to 5° C. in ice, was stirred during its addition to 3-amino-1,2,5,6-tetrahydro-1-oxo-benzo[f]quinazoline (5 g, 0.025 mole)contained in a beaker immersed in an ice bath. The solution was removed from the ice bath, stirred for a further 20 min, then poured onto ice (1000 g). The solid product was removed by filtration, washed with water, and dried under high vacuum at room temperature. The sulfonyl chloride was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1C
Yield: 63.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.045 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+]>CO>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(c1cccc(O)c1)C1CC1

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid (1.45 g) in methanol (20 mL) was added conc. sulfuric acid (75 μL), and the mixture was heated under reflux for 14 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (1.43 g) as a pale-brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](C)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].[OH-:12].[Na+]>O.COCCOC>[CH3:2][CH:3]1[CH:4]([CH2:5][O:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2][OH:1])[O:12]1
Reactant: Cc1cccc(O)c1CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1OC1COc1ccccc1CCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 123.7 %

Procedure:
A mixture of 5.04 g (0.033 mole) of 2-(2-hydroxyethyl)-3-methylphenol, 1.33 g (0.033 mole) of sodium hydroxide in 135 ml of water, and 5.00 g (0.033 mmole) of erythro-(1-bromoethyl)oxirane in 25 ml of 1,2-dimethoxyethane was stirred at room temperature for about 72 hours. The mixture was extracted with 5×100 ml of ether. The extract was washed with dilute sodium hydroxide solution, dilute brine and saturated brine, dried over MgSO4 and concentrated in vacuo to give 4.25 g (58%) of 2-methyl-3-[2-(2-hydroxyethyl)phenoxymethyl]oxirane. A 1:1 (v/v) mixture of 1-methylethylamine and water (130 ml) was added to the oxirane and the mixture was heated at reflux for 5 hours, and concentrated in vacuo to dryness. The residue was dissolved in ether, dried over MgSO4 and concentrated to dryness to give 2.90 g of oil. The oil was flash chromatographed on a silica gel column by elution with 3% CH3OH in CHCl3 saturated with ammonia gas to give 0.5 g of product. Conversion to the oxalate salt gave material with m.p. 138°-140° C. (0.5 isopropanol solvate).