Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)#[CH:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:22]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[CH:4][CH:3]=1)#[CH:23]
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)nc1)C2
Reactant: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)cn1
Yield: 57.2 %

Procedure:
Sonogashira coupling of bromide 52 (see Example 2F) (0.310 g, 0.873 mmol) and ethynyltrimethylsilane (0.61 mL, 4.3 mmol) at room temperature for 18 h, followed by desilylation with TBAF, as in Example 2U, gave (6S)-6-[(6-ethynyl-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (130) (0.150 g, 57%) as a white solid: mp 168-170° C.; 1H NMR [(CD3)2SO] δ 8.51 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.74 (dd, J=8.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 0.6 Hz, 1H), 4.73 (d, J=12.6 Hz, 1H), 4.70 (d, J=12.6 Hz, 1H), 4.67 (dt, J=12.3, 2.3 Hz, 1H), 4.47 (d, J=11.9 Hz, 1H), 4.29 (s, 1H), 4.20-4.28 (m, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH:7]([C:13]([CH3:15])=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>ClCCCl>[CH3:1][NH:2][C:3]1[S:4][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([CH3:15])[N:5]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1sc(NC)nc1C
Yield: 97.5 %

Procedure:
3.6g of methyl thiourea and 7.9g of ethyl 2-chloroacetoacetate were added to 100ml of 1,2-dichloroethane and the mixture was stirred under reflux for 10 hours. After removing the solvent under reduced pressure, 10% aqueous sodium hydroxide solution was added thereto to recrystallize the resulting product which was then filtered to obtain 7.8g (Yield 96%) of ethyl 2-methylamino-4-methyl-thiazole-5-carboxylate as a pale yellow solid. The obtained solid product was dissolved in 60ml of a mixed solvent of methanol-distilled water (v/v=3/1) containing 1.8g of sodium hydroxide. The reaction mixture was stirred under reflux for 8 hours, evaporated under reduced pressure to remove methanol and then adjusted to pH 2 to 3 by adding 10% aqueous hydrochloric acid solution to precipitate the white solid. The precipitated solid product was filtered, washed with water and diethylether and then dried to obtain 6.0g (Yield 90%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc2sc(N)nc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)cccc2s1
Reaction time: 0.17 h

Procedure:
2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly treated with methyl chloroformate (10.6 ml, 137 mmol) at 0° C. After 10 minutes, further methyl chloroformate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the mixture is poured into 200 ml 1M aqueous hydrochloric acid, the organic layer is separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase is dried and the solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS: m/e=238 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccccc21
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCOc2ccccc21
Yield: 63.8 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)chroman-4-amine (0.3 g, 0.93 mmol), piperazine (0.80 g, 9.33 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.74 mmol) in acetonitrile (15 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 0.23 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 144 mg (40%) of N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)chroman-4-amine: 1H NMR (400 MHz, CD3Cl): δ 7.63 (d, 1H), 7.31 (d, 1H), 7.28 (m, 1H), 6.91 (m, 1H), 6.85 (d, 1H), 6.47 (d, 1H), 6.42 (d, 1H), 6.21 (s, 1H), 4.80 (br s, 2H), 4.65 (m, 1H), 4.23 (m, 2H), 3.04 (m, 4H), 2.88 (s, 3H), 2.21 (m, 2H), 2.20 (br d, 1H). MS (ESI) m/z: Calculated: 387.16; Observed: 388.2 (M++1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2]>O.NN.C(O)C>[NH2:7][CH2:6][P:4]([CH2:18][CH:19]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)OCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CN)CC(CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
3 g (6.4 mmol) of benzyl 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4 -methylvalerate were dissolved in 39 ml (12.8 mmol) of a 0.33M solution of hydrazine hydrate in ethanol. The solution was stirred at room temperature overnight. The solvent was removed by evaporation and traces of hydrazine were removed by treatment with toluene followed by evaporation. The residue was taken up in 50 ml of dichloromethane and stirred at room temperature for 45 minutes in the presence of 5 ml of glacial acetic acid. The solid was removed by filtration and the filtrate was evaporated to give 2.56 g of benzyl 2(RS)-[[(RS) -(aminomethyl)(ethoxy)phosphinyl]methyl]-4-methylvalerate in the form of a gum.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:9]([C:24]#[N:25])[CH:8]=1)([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]2)=[C:9]([C:24]#[N:25])[CH:8]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Ammonium chloride (2.1 g) and iron powder (11.1 g) were added to a mixed solvent of water (110 ml) and ethanol (30 ml), and the mixture was heated to 65° C. Then, ethyl 1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (12 g), melting point: 98° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cn3ccc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
To a mixture of indole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-indol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (6 mg, 18%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 7.97 (br. s., 1H), 7.82 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.94-7.14 (m, 2H), 6.49 (d, J=3.0 Hz, 1H), 5.49 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[CH:33]=[N:34][C:35]([O:37][Si](C)(C)C)=[CH2:36]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:36][C:35](=[O:37])[NH:34][CH:33]2[C:27]2[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:26]=2[CH3:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1c(C)cccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1c(C)cccc1C
Yield: 70.6 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.08 mmol) prepared in example 4b was reacted with 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.9 g, 11.7 mmol) prepared in example 27a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.41 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)ccc1Oc1ccccc1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a stirring compound of the title compound of Example 9 (5.0 g, 23 mmol) in pyridine (50 mL) was added acetic anhydride (2.75 g, 27 mmol), and the resulting solution was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in CHCl3 (300 mL) and extracted with HCl (1M, 3×150 mL), NaHCO3 (saturated, 3×150 mL), dried (MqSO4) and evaporated to yield an oil. The material was chromatographed (MPLC, 1:1 EtOAc:hexane) to yield 4.52 g of a yellow oil. This material was employed in Example 11 without further purication.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH2:6].[N:19]1[CH:24]=[C:23]([C:25]([NH:27][C:28]2([C:31](O)=[O:32])[CH2:30][CH2:29]2)=[O:26])[CH:22]=[N:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH:6][C:31]([C:28]1([NH:27][C:25]([C:23]2[CH:22]=[N:21][CH:20]=[N:19][CH:24]=2)=[O:26])[CH2:30][CH2:29]1)=[O:32]
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: COc1ccc(Oc2ccc(CN)cc2F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.7 mg (0.1 mmol) of 3-fluoro-4-(4-methoxy-phenoxy)-benzylamine were dissolved in 1 ml DMF. 20.7 mg (0.1 mmol) of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (prepared in 1b) were also dissolved in DMF and 35.3 mg (0.11 mmol) and 21 μl triethylamine (0.15 mmol) were added. Shaken overnight at ambient temperature and purified by reversed-phase chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([O:24]C(C)(C)C)=O)[C@H:19]([C:29]([O:31]C)=[O:30])[CH2:18]1)(=[O:16])=[O:15].[Cl:33][C:34]1[CH:35]=[C:36]([F:46])[C:37]([C:40]2(C(O)=O)[CH2:42][CH2:41]2)=[N:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([F:46])[C:37]([C:40]2([C:22]([N:20]3[CH2:21][C@H:17]([S:14]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:7][C:2]=4[Cl:1])(=[O:16])=[O:15])[CH2:18][C@H:19]3[C:29]([OH:31])=[O:30])=[O:24])[CH2:41][CH2:42]2)=[N:38][CH:39]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C1(c2ncc(Cl)cc2F)CC1
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to General Procedure C, steps C4-C6, using (2S,4R)-1-tert-butyl 2-methyl 4-(2-chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl)pyrrolidine-1,2-dicarboxylate in step C4, and 1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid in step C5. MS (m/e)=584.9 [M+H+].
Reaction SMILES: O.[Si:2]([O:19][CH2:20][C@:21]12[C@H:27]([O:28]CC3C4C(=CC=CC=4)C=CC=3)[C@H:24]([O:25][CH2:26]1)[C@H:23]([N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])[O:22]2)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[Si:2]([O:19][CH2:20][C@:21]12[C@H:27]([OH:28])[C@H:24]([O:25][CH2:26]1)[C@H:23]([N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])[O:22]2)([C:15]([CH3:17])([CH3:16])[CH3:18])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2OCc1cccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Water (23 mL) was added to Compound 109 (11.8 g) dissolved in CH2Cl2 (120 mL) and the biphasic solution was stirred at room temperature. To this stirring solution was added DDQ (9.2 g) and the reaction mixture was stirred for 7 h at which point the reaction was complete. The reaction mixture was diluted with dichloromethane (500 mL) and it washed with 2% aqueous sodium bisulfite solution. The organic layer was separated and the aqueous layer was extracted several times with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate solution (5×300 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was purified by using 30% EtOAc in CH2Cl2 followed by 10% MeOH in CH2Cl2. Compound 110 obtained in a 96% yield as colorless pallets after removing the solvent.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]#[N:11].Cl.[OH2:14]>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]([NH2:11])=[O:14]
Reactant: N#CC(=O)c1ccccc1CCl
Reactant: O
Agent: Cl
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 40 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A mixture of 2-(2-chloromethylphenyl)-2-oxoacetonitrile (1.80 g) and 36% hydrochloric acid aqueous solution (10 ml) was stirred at 40° C. for 20 hours. After the mixture was cooled by allowing it to stand, ice-cooled water was added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate twice. The combined ethyl acetate layer was washed successively with a saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a crude product (0.89 g). The crude product was recrystallized from ethyl acetate-hexane to give the title compound (0.80 g, yield: 40.2%, pale yellow crystals).
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O>C(OCC)(=O)C>[CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN[C@H](C)[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
The hydroxy acid obtained above, 18.43 g. (0.093 mole) was dissolved in 200 ml. of ethyl acetate with gentle warming and to the solution was addeda solution of 15.04 g. (0.91 mole) of d-ephedrine, [α]578 =(+)11.4 (acetone), in 80 ml. ethyl acetate. The mixture was stirred at room temperature over night during which time a crop of crystals formed, was removed by filtration and air dried to obtain 18.3 g., M.P. 97°-99° C. This material was recrystallized by dissolving itin a minimum amount of hot ethyl acetate and allowing to stand at ambient temperature over night. After three such recrystallizations, 8.9 g. of thed-ephedrine salt of l-4-hydroxy-4-(p-fluorophenyl)butyric acid, M.P. 105.5°-106.5° C. was obtained.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1.[CH2:22]([SH:24])[CH3:23].O>CN1C(=O)CCC1>[CH2:22]([S:24][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:23]
Reactant: FC(F)(F)c1ccc2sc(-c3sccc3Br)nc2c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.11 g of sodium hydride (60%) was added to a solution of 0.65 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethyl)benzothiazole and 0.15 ml of ethanethiol in NMP 6 ml 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.61 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethyl)benzothiazole (Compound of Present Invention (37)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](OC(=O)C)[O:11]C(=O)C)=[C:6]([O:19][CH3:20])[CH:5]=1)([O-:3])=[O:2].O1CCOCC1.Cl>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([O:19][CH3:20])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C(OC(C)=O)OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1C=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To a 2 L rounded bottom flask equipped with a condenser and a mechanical stirrer was placed 1A (250.7 g,0.8851 mol), dioxane (300 mL) and concentrated HCl (60 mL). The reaction mixture was heated to reflux and stirred under N2 for 20 hours. Water (250 mL) was added dropwise while maintaining the reaction mixture at reflux. After cooling to 0° C. with an ice/water bath, the resulting slurry was stirred for 30 minutes and then filtered. The cake was washed with water (4×200 mL) and suction dried for 17 hours to give 1B (I146.3 g, 91%) as yellow solid. 1H NMR (CDCl3) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:38][CH2:37][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCCC1CCCCC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCC5CCCCC5)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 68 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-cyclohexylethanol according to Method E (yellow solid, 172 mg, 0.325 mmol, 68% yield). ES HRMS m/z calc. for C32H37ClN3O2 (M+H) 530.2569, found 530.2534.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27].Cl>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH2:29][CH2:28][C:26](=[O:27])[CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reactant: C=CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1C=C2CCN(Cc3ccccc3)CC2(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1,3-Dibenzylpiperidin-4-one (3, Y═H, Z=benzyl (3.98 g, 13.96 mmol) was added to a solution of sodium methoxide (0.83 g, 15.36 mmol) in 80 mL of methanol and stirred at ambient temperature for 45 min. The contents were cooled to 0° C. and methylvinyl ketone (1.74 mL, 20.94 mmol) was added over 30 min. The contents were allowed to warm to ambient temperature and stir for 18 h. Concentrated HCl (1.55 mL) was added, the contents were stirred for a further 5 min and the solvents were evaporated to give a brown oil which was triturated in diethyl ether to give the title compound, 1.90 g. LC-MS: RT=2.26 min. (M+H)+ 332.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CN(C)C=O>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)C12CC1CCC2=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
In argon atmosphere, potassium cyanide (260 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to dimethylformamide (3 ml). The mixture was stirred at the room temperature for 24 hours and was treated in accordance with the process of Preparation 4 to obtain 290 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 53%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].C(Cl)Cl.Cl.[CH3:11][NH:12][O:13][CH3:14]>O>[CH3:14][O:13][N:12]([CH3:11])[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 2-methoxyacetyl chloride (10 g, 92.1 mmol) and DCM (100 mL) cooled to 0° C. was added N,O-dimethylhydroxylamine hydrochloride (9.89 g, 101 mmol) and TEA (38.5 mL, 276 mmol) and the reaction warmed to RT and stirred for 18 h. The reaction mixture was poured into H2O and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 12 g (97.8%) of N,2-dimethoxy-N-methylacetamide.