Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)=O)(C)(C)C.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1.[CH2:24]([CH2:27]OC)[O:25]C>C(N(CC)CC)C>[CH2:24]([O:25][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][O:17][C:21](=[O:22])[CH2:20][C:19]([CH3:18])=[O:23])[C:27]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: C=C1CC(=O)O1
Reactant: COCCOC
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCc1ccccc1OCc1ccccc1

Procedure:
A solution of 4.9 g of 1-benzyloxy-4-(2-hydroxyethyl)benzene (8) in 100 mL of dimethoxyethane (DME) and 5 drops triethylamine was heated to reflux and 1.8 mL of diketene was slowly added. The solvent was removed under reduced pressure to yield 6.4 g of 2-(benzyloxyphenyl)ethylacetoacetate (9), m.p. 54°-56° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[O:12]1CCOCC1>>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:1]=[O:12]
Reactant: C1COCCO1
Reactant: Cc1ccc2ncccc2n1
Product: O=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-1,5-naphthyridine (8-2) (2.9 g, 20.1 mmol) and SeO2 (2.2 g, 20.1 mmol) in 40 mL of dioxane was refluxed for 3 h. After cooled to room temperature, the reaction mixture was concentrated. The residue was treated with brine and extracted with DCM/i-PrOH=4/1. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by chromatography on silica gel to afford the title compound (1.81 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.O>ClCCl>[CH:6]([N:8]1[CH2:13][CH2:12][N:11]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=CN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(C=O)CC1

Procedure:
3.5 mL of methane sulfonylchloride in 50 mL of dichloromethane was added slowly to a solution of 4.9 g of 1-formylpiperazine and 6.1 mL of triethylamine in 100 mL of dichloromethane at 0° C. After stirring for 1 hour water was added and the organic layer was separated. The aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated to yield 5.8 g of 1-formyl-4-(methylsulfonyl)piperazine. The crude product was dissolved in 15 ml of ethanol and 15 mL of aqueous 2N NaOH and stirred for 1.5 hours at 80° C. After cooling to room temperature water was added and extracted several times with dichloromethane. The combine organic layers were dried (MgSO4) and concentrated to give 2.9 g of the title compound 14b. 1H-NMR 200 MHz (DMSOd6) δ: 2.70-2.77 (4H, m), 2.83 (3H, s), 2.95-3.02 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29]OS(C)(=O)=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:42]4[C:41](=[O:43])[C:40]5=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]5[C:38]4=[O:48])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.26 g), and the mixture is stirred at 110° C. for one hour. The mixture is poured into ice-water, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography to give 7-chloro-1-[6-(6,7-benzo-1-oxo-4-azepin-5-on-4-yl)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g, Compound A) and 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g, Compound B), separately.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH2:13][CH:14]3[CH2:23][CH2:22][N:21]4[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:15]3)=[O:11])=[CH:2]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN2CCCCC2C1)c1cn(CC2CCCCC2)c2ccccc12

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was alkylated with cyclohexylmethyl bromide using the method of Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford a colourless oil, which crystallised from n-pentane to give the title compound (E29) as a white solid mp 98°-100° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.81 ml) was added to a solution of N-(4-hydroxy-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (3.32 g) and N,N-dimethylformamide (6 drops) in chloroform (20 ml) at room temperature. The mixture was stirred at 40° C. for 1 hour, washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (4.12 g) as oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:56]=[CH:55][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(=O)CN(C)CC(=O)O3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:56][CH:55]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 82 %

Procedure:
A mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1.0 g, 2.13 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (0.87 g, 2.434 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.175 g, 0.426 mmol) and 2M K3PO4 (7.99 mL, 15.98 mmol) in 1,4-Dioxane (200 mL) and Water (40.0 mL) was degassed for 10 min. Then, PdOAc2 (0.048 g, 0.213 mmol) was added, degassed for 5 min and mixture was heated at 80° C. for 3 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated the residue was then purified by Biotage (5-40% EtOAc/hexane) to afford (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (1.056 g, 82% yield) as white foam. 1H NMR (500 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.18-7.14 (m, 1H), 7.09-7.01 (m, 3H), 6.99-6.93 (m, 2H), 6.07 (br. s., 1H), 5.10 (spt, J=6.2 Hz, 1H), 4.28-4.19 (m, 2H), 3.21 (d, J=12.0 Hz, 1H), 3.13 (t, J=6.9 Hz, 2H), 2.87 (t, J=12.1 Hz, 1H), 2.60 (s, 3H), 2.28 (d, J=12.8 Hz, 1H), 2.20 (s, 3H), 2.10-2.01 (m, 1H), 1.60-1.52 (m, 1H), 1.42-1.34 (m, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 1.20 (s, 9H), 1.08 (d, J=12.3 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). 1H of piperidine was not resolved. LCMS (M+H)=606.5.
Reaction SMILES: [ClH:1].N1C=CC=CC=1.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=3)[C:19]=2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:33][CH:32]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[ClH:1].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:33][CH:32]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Cc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 200 °C
Yield: 79.3 %

Procedure:
Add pyridine hydrochloride (4 g) to the compound of Example 77 (110 mg, 0.21 mmol). Purge with nitrogen, cap the vessel and heat to 200° C. for 2 hours. Cool the reaction mixture and dilute with saturated aqueous NaHCO3. Extract with CH2Cl2, dry over Na2SO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% MeOH/CH2Cl2). Dissolve the product in 1:1 CH3CN/1M aqueous HCl and lyophilize to afford 92 mg of the title compound (80%). LCMS: m/z=516 (M+H)+—HCl.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([NH2:35])[CH3:34]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:35][CH2:33][CH3:34])=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A solution of 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole in THF (4.0 mL, 0.095 mmol) (see following step B for preparation) was added to a solution of ethylamine (100 uL, 2.0 M in THF, 0.2 mmol) in THF (2.0 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with EtOAc (50 mL), washed with NaHCO3 (2×5 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 21 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.02 (t, J=7.13 Hz, 3 H), 1.51-1.64 (m, 2 H), 1.66 (s, 9 H), 1.69-1.87 (m, 4 H), 2.01-2.15 (m, 2 H), 2.21-2.37 (m, 1 H), 3.04 (q, J=7.16 Hz, 2 H), 3.62 (dd, J=8.11, 6.74 Hz, 2 H), 3.99 (t, J=8.10 Hz, 2 H), 4.16-4.29 (m, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.59, 1.56 Hz, 1 H), 8.03 (d, J=8.59 Hz, 1 H), 8.17 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=512.3; Anal. Calcd for C24H35F2N5O3S+1.40 TFA+0.50H2O (680.28): C, 47.32; H, 5.54; N, 10.29. Found: C, 47.36; H, 5.57; N, 10.32.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([C:19]2[C:20]3[N:21]([CH2:36][CH2:37][N:38]=3)[C:22]3[C:27]([N+:28]=2[O-:29])=[CH:26][CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:23]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH3:1][S:2]([N:33]1[CH2:34][CH2:35][N:30]([C:24]2[CH:23]=[C:22]3[C:27]([N+:28]([O-:29])=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:20]4[N:21]3[CH2:36][CH2:37][N:38]=4)=[CH:26][CH:25]=2)[CH2:31][CH2:32]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A solution of methanesulfonyl chloride (0.33 g, 0.003 mol) in dichloromethane (20 ml) was cooled in an ice-bath. To this solution was added dropwise with stirring, a solution of triethylamine (0.29 g, 0.003 mol) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1 g, 0.003 mol) in dichloromethane (10 ml). The reaction mixture was stirred for an additional 15 minutes and then was allowed to warm to room temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulphate and then evaporated to dryness under reduced pressure to yield a yellow solid. Recrystallization from ethyl acetate yielded 1,2-dihydro-8-(4-(methylsulphonyl)piperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (0.8 g), as yellow crystals, m.p. 252°-253° C. (Found: C,59.19; H,5.35; N,16.33%; C21H23N5O3S requires C,59.29; H,5.41; N,16.47%) having the formula: ##STR31##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2ccc(Br)cc2n1
Product: Clc1ncc2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 65 %

Procedure:
A 0.5M suspension of 7-bromoquinazolin-2-ol in phosphorus oxychloride was heated to 110° C. in an oil bath for 1 h. The mixture was cooled to room temperature. Volatiles were removed under reduced pressure. The residue was triturated with ice water. The solid was collected by filtration and air dried to give product in 65% yield. ES/MS m/z 243/245 (MH+).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2N=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[O:41])[CH3:40])=[N:37][CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[CH:1]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)([OH:41])[CH3:40])=[N:37][CH:38]=1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)cc(-c2cnc(C(C)(O)c3ccc(Br)cn3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
THF (20 ml) was cooled to −78° C., and lithium diisopropylamide (7.64 ml, 13.75 mmol) was added. N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 1.85 g, 5.50 mmol) in THF (15 ml) was added drop wise, and the reaction was stirred at −78° C. for 30 min. 1-(5-Bromopyridin-2-yl)ethanone (1.100 g, 5.50 mmol) in THF (5 ml) was subsequently added in one portion. The reaction was stirred for 10 min at −78° C. The dry ice bath was removed, and the reaction was allowed to warm to room temperature. The dark brown reaction mixture was quenched with aqueous saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (Biotage 100 g SNAP, 0-20% EtOAc/toluene) afforded 1-(5-bromopyridin-2-yl)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyridin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (1.487 g, 2.77 mmol, 50.4% yield) as a yellow solid. MS ESI: [M+H]+ m/z 538.0.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
The product from Example 126b (4.0 g, 13.6 mmol) in 40 mL of CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound as a yellow oil (4.2 g, 100%).
Reaction SMILES: [OH-:1].[CH2:2]([N+](C)(C)C)[C:3]1[CH:8]=CC=CC=1.[C:13]([CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])[NH2:14].O>C(#N)C>[OH:1][CH:2]1[NH:14][C:13](=[O:15])[C:16]2([C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:3]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-benzyltrimethylammonium hydroxide (Triton B) which is a 40% methanolic solution (3.5 ml) in acetonitrile (10 ml) was added dropwise over 0.25 hour to a suspension of 9-carbamoylfluorene (20.9 g) in acetonitrile (100 ml) keeping the temperature below 25° C. The reaction mixture was stirred at room temperature for 2 hours. Water (300 ml) was then added slowly over 1 hour and the crystallised product was isolated by filtration, washed with water and dried in vacuo overnight at 50° C. 89%, melting point 201°-205° C. (decomp). The product was identical spectroscopically to that prepared in Example 1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=O.[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[N:16]=1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2ccc3c(c2)CCC(=O)N3)cs1
Reaction time: 0.5 h

Procedure:
6-(Chloroacetyl)-3,4-dihydrocarbostyril (7 g), thiourea (2.6 g) and absolute ethanol (250 ml) is stirred under reflux for two hours, cooled in an ice bath, filtered, and the filtered solid washed with ether and dried. The solid is suspended in aqueous sodium bicarbonate and stirred for 30 minutes, filtered, washed with isopropanol, dried and refluxed in methanol (300 ml) overnight. The resulting solid is filtered, suspended in boiling methanol (300 ml) and methane sulfonic acid (2.8 ml) added, resulting in the formation of a precipitate which is filtered, twice recrystallized from ethanol/DMF affording the desired product as the methane sulfonic acid salt, M.P. >250° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=3[C:28]3[CH:29]=[C:30]([C:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44]C)=[O:43])[CH2:38][CH:37]=4)[CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+].Cl>O1CCOCC1.O.CCOC(C)=O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=3[C:28]3[CH:29]=[C:30]([C:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH:37]=4)[CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COC(=O)C1CC=C(c2ccc(OC)c(C3=C(CN4C(=O)O[C@H](c5cc(C(F)(F)F)cc(C(F)(F)F)c5)[C@@H]4C)CC(C)(C)CC3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CCC(C(=O)O)CC2)cc1C1=C(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
According to the same method as the synthesis of Compound 354, the obtained methyl 4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)cyclohex-3-enecarboxylate was dissolved in dioxan/water (5 mL, v/v 2:1). Lithium hydroxide (10 mg) was added dropwise to the obtained solution at room temperature, and stirred at room temperature for 5 hours. After the completion of the reaction, the reaction mixture was acidified with 2 M HCl solution. The reaction mixture was diluted with EtOAc, was washed with water and brine. The organic layers were collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by MPLC (3:1 hexane:EtOAc), thus obtaining Compound 362 (30 mg, 24%) as white solid foam.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=O.[CH3:19][O:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:25])/[CH3:24]>CC(O)=O>[CH3:19][O:20][C:21](=[O:26])[C:22]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[N:25][C:23]=1[CH3:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: CN(C)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
5.57 g (19.76 mmol) of the above prepared 3-dimethylamino-1-(3-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 2.28 g (1.00 eq.) of 3-aminocrotonic acid methyl ester were dissolved in 60 ml of AcOH and heated to reflux for 4 h. After cooling, the bulk of the solvent was evaporated i. V., the residue dissolved in AcOEt and washed with water and brine. Drying over sodium sulfate, evaporation of the solvents and flash chromatography (SiO2, hexane/AcOEt=89/11) delivered finally 2.00 g of the title compound as light yellow crystals of mp. 47-49° C. (dec.).