Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[C:16]2[C:7]([NH:8][C:9]3[C:14]([S:15]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=12.[CH3:22][O:23][CH2:24]Cl.C(OCC)C>C1COCC1.O>[CH3:22][O:23][CH2:24][O:3][C:4]1[CH:17]=[C:16]2[C:7]([NH:8][C:9]3[C:14]([S:15]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=12
Reactant: COCCl
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc2c(c3ccccc13)Nc1ccccc1S2
Reaction time: 0.25 h

Procedure:
Sodium hydride (75 mg) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1) (500 mg) and chloromethyl methyl ether (154 mg) in THF (10 ml) and the reaction mixture was stirred for 15 minutes. Diethyl ether (60 ml) was added to the reaction mixture followed by water (60 ml). The ether layer was decanted, dried and evaporated to dryness. The resulting residue was chromatographed on silica gel (CH2Cl1 /hexane (7:3)) to afford the title compound, m.p. 103° C. Anal. C18H15NO2S; Calcd.: C, 69.87; H, 4.89; N, 4.53; S, 10.36. Found: C, 69.75; H, 5.01; N, 4.41; S, 10.53.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:47]([N:10]1[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OCCOc1nn(Cc2ccccc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(Cc3ccccc3)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a stirring solution of 2-{[1-benzyl-5-(bis{[4-(tert-butyl)phenyl]sulfonyl}amino)-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 40) (1.01 g) in ethanol (20 ml) was slowly added sodium hydroxide solution (2M, 2 ml). The reaction mixture was left stirring at room temperature overnight. The solvent was removed in-vacuo and the residue was taken up in ethyl acetate (30 ml) and washed with water (15 ml) followed by brine (1 ml). It was then dried (MgSO4) and the solvent removed in-vacuo to yield the crude material as a yellow oil (ca.1 g). Purification was achieved using the Biotage™ Flash 40 system (silica, 90 g) with a gradient elution of hexane (75% to 65%) and ethyl acetate (25% to 35%) to yield the title product as a yellow solid (250 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:14]=[N:13][N:12]([C@H:15]3[C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]3)[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[F:29][C:30]1[CH:31]=[C:32]([C@@H:37]2[CH2:39][C@H:38]2[NH2:40])[CH:33]=[CH:34][C:35]=1[F:36].C(N(CC)C(C)C)(C)C.O>ClCCl>[F:29][C:30]1[CH:31]=[C:32]([C@@H:37]2[CH2:39][C@H:38]2[NH:40][C:2]2[C:3]3[N:14]=[N:13][N:12]([C@H:15]4[C@@H:19]5[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]5[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]4)[C:4]=3[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Yield: 93 %

Procedure:
A solution of 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (370 mg, 0.86 mmol, 1.00 equiv) (15 mL), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21 mmol, 1.20 equiv.) in dichloromethane was stirred at ambient temperature for about 16 hours, and then water (10 mL) was added. Standard extractive workup with dichloromethane (3×10 mL) gave the title product as a yellow oil (450 mg; yield=93%). m/z=563 (MH)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:31].[CH3:33][C:34]1[C:42]2[C:37]([NH:38][CH:39]=[N:40][C:41]=2[N:43]2[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]2)=[N:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl.CN1CCCC1=O>[ClH:31].[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:49][CH:46]1[CH2:45][CH2:44][N:43]([C:41]2[C:42]3[C:34]([CH3:33])=[CH:35][NH:36][C:37]=3[N:38]=[CH:39][N:40]=2)[CH2:48][CH2:47]1)=[O:15]
Reactant: ClCCCl
Reactant: Cc1cnc2[nH]cnc(N3CCC(N)CC3)c1-2
Reactant: C[C@@H]1CCCN1CCOc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4cccc(OCCN5CCC[C@H]5C)c4)CC3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-({2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}oxy)benzoic acid D54 (116 mg), HOBT (119 mg, 0.778 mmol) and EDC (149 mg, 0.778 mmol) in Dichloromethane (DCM) (15 mL) stirred at 25° C. was added a solution of 1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D11a (90 mg, 0.389 mmol) and DIEA (201 mg, 1.556 mmol) in N-Methyl-2-pyrrolidone (NMP) (5 mL). The reaction mixture was stirred at 25° C. overnight. Then the mixture was washed with water (30 ml) and the organic layer was separated. The aqueous layer was extracted with DCM (20 ml×2) and the combined organic layer was concentrated.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].O.[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15]C=1C(O)=O>C(Cl)Cl.CN(C)C=O>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.81 ml) in methylene chloride (10 ml) was added dropwise to a solution of 2-methoxy-4-nitrobenzoic acid monohydrate (1 g) in methylene chloride (40 ml) and dimethylformamide (1 drop) and the reaction mixture was stirred at room temperature for 1 hour after gas evolution ceased. The solvent was then evaporated in vacuo to give an oil which was crystallised from cold ethyl acetate/hexane to give the title compound, yield 0.7 g.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5].C(N(CC)CC)C.[CH3:22][SH:23]>CCOCC>[CH3:22][S:23][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: CS
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CSC(C)CC(=O)C1=C(C)C=CCC1(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 50 ml, three-necked, round-bottom flask equipped with a magnetic stirring assembly, a tube submerged for the introduction of gas, an immersion thermometer and a dry ice isopropanol condenser, the outlet of which leads through a 50% alkali trap to the hood sink, is placed 8.3 grams of beta-damascenone and approximately 1 gram of triethylamine. Gaseous methyl mercaptan is introduced into the stirred reaction mixture which is maintained at 10° C. Addition is continued for approximately one hour and then stopped. The stirred reaction mix is allowed to attain room temperature, and the reaction mix is stirred overnight at room temperature. The next morning the light yellow reaction mix is transferred to 50 ml of ether in a separatory funnel and washed twice with dilute sulfuric acid, twice with saturated sodium bicarbonate solution, and then with saturated saline solution until the wash is neutral. The dried ether layer is stripped of solvent on a `rotovap` and GLC of the residue on an 1/8'×10" stainless steel, 5% carbowax 20 M column isothermally at 190° C. shows one major late eluting peak which is trapped for infra-red and nuclear magnetic resonance/mass spectral analyses. Infra-red analysis suggests that the cyclohexadienyl ring structure is intact and in conjugation with the side chain ketone which is, however, now out of cross conjugation. Therefore, reaction appears to have occurred at the side chain olefinic site. Mass spectral analysis shows a molecular weight of 238, and the proper fragmentation for the proposed structure. The mass spectral analysis also is a satisfactory match with the scan for peak "A" as set forth in Example I. This peak has an IE on SE-30 of 13.00. A trap of the synthetic material is run for IE and the IE on SE-30 is 13.08.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[N:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 65 °C
Reaction time: 16 h
Yield: 16.9 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (0.530 g, 2.35 mmol,) in acetonitrile (25 mL) was added 5-chloro-2-nitro-pyridine (0.561 g, 3.53 mmol,) and powdered potassium carbonate (1.30 g, 9.40 mmol). The reaction mixture was then heated to 65° C. for 4.0 hr, then at 45° C. for 16 hr. The reaction mixture was then allowed to cool to room temperature and filtered through a 10.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 50 mL of (1:1) methanol in dichloromethane, 25 mL of methanol, followed by 7N ammonia in methanol (50 mL). The filtrate was concentrated under vacuum to obtain a compound which was purified again by column chromatography on silica gel eluting with methanol in dichloromethane (0-10%) to afford 0.110 g (17%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][C:20](=[O:22])[NH:21][C:14]=23)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20](=[O:22])[NH:21][C:14]=34)=[CH:4][CH:3]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Yield: 15.2 %

Procedure:
Method H2 was used with 7-(4-aminonaphthalen-1-yl-oxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (94 mg, 0.32 mmol) and 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (77 mg, 0.35 mmol) to afford the title compound as a brown solid (25 mg, 15%). 1H-NMR (6, ppm, DMSO-d6): 6.21 (d, 1H, HPy,5, J=5.9 Hz), 7.20 (m, 1H, Harom,Naph), 7.56-7.67 (m, 4H, Harom,naph+Py,6), 7.79-7.87 (m, 2H, Harom,Ph′), 7.94-7.97 (m, 1H, Harom,naph), 8.23-8.31 (m, 2H, Harom,naph), 10.52 (s, NH, NHPy), 11.26 (s, NH, NHPy). LC-MS (m/z): 514 (M+H, 100).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.Br[CH2:47][CH2:48][CH2:49][CH2:50][Cl:51]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:47][CH2:48][CH2:49][CH2:50][Cl:51])[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: ClCCCCBr
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCCCCl)c3ccccc23)cc1
Yield: 92.6 %

Procedure:
Substantially the same procedure as in Reference Example 2 was repeated using Compound 1 (5.0 g, 7.99 mmol) and 1-bromo-4-chlorobutane (1.0 ml, 8.78 mmol) to give 5.3 g (yield: 93%) of the title compound.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[Cl:47][C:48]12[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][C:50]([CH2:58][OH:59])([CH2:51]3)[CH2:49]1)[CH2:55]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:50]23[CH2:51][CH:52]4[CH2:53][CH:54]([CH2:55][C:48]([Cl:47])([CH2:57]4)[CH2:49]2)[CH2:56]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(Cl)(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(Cl)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-chloroadamantan-1-yl methanol, the title compound was obtained as a colorless solid (0.15 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 3.82 (s, 2H), 2.87 (s, 6H), 2.22 (br s, 2H), 2.14-2.02 (m, 6H), 1.70-1.55 (s, 6H); MS (ES−) m/z 477.1, 479.1 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: C1CCNCC1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCCCC2)c1OCCC(C)c1ccc(F)cc1
Yield: 43 %

Procedure:
Example 8a (90 mg, 0.19 mmol) was reacted with piperidine (8.0 eq.) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica gel, DCM/MeOH 100:0, 49:1) to afford the title compound (40 mg, 43%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.95 (t, J=6.8 Hz, 2H), 3.83 (s, 3H), 3.00 (m, 1H), 2.59 (t, J=6.0 Hz, 3H), 2.50 (s, 3H), 2.45-2.35 (m, 4H), 2.18 (s, 3H), 2.05-1.98 (m, 2H), 1.61-1.54 (m, 4H), 1.46-1.42 (m, 2H), 1.24 (d, J=6.9 Hz, 3H). MS (ES+) m/z 492.3 (M+H+).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:16]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(O)CNC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
To ethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate (3.9 g, 18 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (3.2 ml, 27.2 mmol) dropwise, followed by K2CO3 (7.5 g, 54.3 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 4.2 g product (77%). [M+H] calc'd for C18H27NO3, 306. found 306.
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=2[CH:21]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].Cl>C(O)C.O>[Cl:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=2[CH:21]=1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(Cl)cc21
Reaction time: 3 h
Yield: 18 %

Procedure:
A mixture of 0.41 g of ethyl 6-amino-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate hydrochloride, 0.13 g of sulfuric acid, 0.10 g of sodium nitrite and 12 ml of H2O was stirred under ice-cooling for 1 hour. The reaction mixture was added dropwise to a mixture of 0.30 g of cuprous chloride and 10 ml of concentrated HCl under ice-cooling, then the mixture was stirred at room temperature for 3 hours followed by 3 hours at 70° C. with heating. Added 2N HCl to the reaction mixture and extracted with ethyl acetate. The resultant organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. To the residue thus obtained added a mixture of 50 ml of ethyl alcohol and 2 ml of sulfuric acid and refluxed with heating for 2 hours. The reaction mixture was concentrated in vacuo to half a volume, added water to the residue and extracted with methylene chloride. The resultant organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue thus obtained was purified with silica gel column chromatography (developing solution, ethyl acetate:hexane=1:10) to obtain 0.07 g of ethyl 6-chloro-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate with a melting point of 76°-78° C.
Reaction SMILES: C([O:4][C@H:5]([CH3:35])[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[N:13]=1)=[O:7])(=O)C.O.[OH-].[Na+]>CO>[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[N:13]=1)(=[O:7])[C@@H:5]([CH3:35])[OH:4]
Reactant: CC(=O)O[C@H](C)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](O)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To an ice-cooled mixture of 2-((2R)-2-acetoxypropionylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (2.1 g), water (4 ml) and methanol (17 ml) was added dropwise 1N sodium hydroxide solution (3 ml). After the addition had been completed, the reaction mixture was kept at 5° C. for 1 hour and allowed to warm to ambient temperature. After standing overnight at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (30:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with 70% ethanol to give white powder. Recrystallization from 70% ethanol gave 2-(D-lactoylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (1.13 g).
Reaction SMILES: [CH:1]12[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31)[CH2:5][NH:4][CH2:3][CH2:2]2.C(=O)(O)[O-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].[ClH:24]>CCOCC.CO>[ClH:24].[CH2:22]([N:4]1[CH2:3][CH2:2][CH:1]2[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=32)[CH2:5]1)[CH:21]=[CH2:20]
Reactant: c1ccc2c(c1)CC1CNCCC2C1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C=CCN1CCC2CC(Cc3ccccc32)C1

Procedure:
1.87 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine, 1.25 g of sodium bicarbonate and 1.33 g of allyl bromide were added into 30 ml of methanol, and the mixture was refluxed for 5 hours and subjected to distillation under reduced pressure. The residue was dissolved in 15 ml of 10% hydrochloric acid. The solution was washed once with 5 ml of benzene, and the water layer was made alkaline with sodium hydroxide and extracted with ether. Ether was distilled from the ether extract and the residue was subjected to vacuum distillation to obtain 2 g of a colorless oily substance as a fraction boiling at 110° to 120° C. (bath temperature) under 0.7 mmHg. The product was dissolved in 15 ml of ether and gaseous hydrochloric acid was blown into the solution to form a white precipitate. The precipitate was recovered by filtration and dried to obtain 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. Recrystallization from isopropanol gave a white crystalline powder melting at 212.5° to 214.5° C.