Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH3:17].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 91.6 %

Procedure:
Ferulic acid (4.85 g) and then n-propyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux overnight. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (5.48 g, 91.6%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2F)cn1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A suspension of [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (125 mg, 0.50 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253 mg, 1.00 mmol) in ethanol (4 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane and then dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (200 mg, 99%) as a white solid. MS ISP (m/e): 405.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.40 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.38 (t, 1H), 7.32 (t, 2H), 7.10-7.21 (m, 4H), 4.04 (m, 1H), 2.70 (m, 2H), 2.13 (s, 3H), 2.11 (m, 1H), 1.70-1.89 (m, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8](/[CH:20]=[CH:21]/[C:22](=[O:31])[C:23]([F:30])([F:29])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:31])[C:23]([F:29])([F:30])[CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C@H:7]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC[C@H](C)CC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H](C)CC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Yield: 94.3 %

Procedure:
To a solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (76.78 g, 141.0 mmol) in ethyl acetate (357 ml), 5%-palladium on carbon (7.30 g) was added and the solution was hydrogenated at room temperature and the ambient pressure. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((6S)-4,4-difluoro-6-methyl-3-oxooctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (D) (72.69 g; 133.0 mmol; yield: 94.3%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=O)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29](=[O:31])[NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A solution of 0.415 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide in 0.25 ml of dimethylformamide was treated with 0.461 g of O-benzylhydroxylamine and 0.173 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.160 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][C:35]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O.[NH2:77][C:78]1[NH:82][N:81]=[N:80][N:79]=1>CN(C=O)C>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:42]=[CH:41][C:37]([C:38]([NH:77][C:78]6[NH:82][N:81]=[N:80][N:79]=6)=[O:39])=[CH:36][C:35]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ncc(-c2ccc(C(=O)Nc3nnn[nH]3)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (EXAMPLE 39, 195 mg, 0.276 mmol), EDC (106 mg, 0.55 mmol), HOBt (56 mg, 0.42 mmol), and DIEA (96 μl, 0.55 mmol) in DMF (2 mL) was added 5-aminotetrazole monohydrate (144 mg, 1.38 mmol). After stirring at 40° C. for 8 hours, the reaction mixture was directly applied to reverse phase HPLC, eluting with 10% to 100% acetonitrile in water, to obtain the title compound (160 mg, 57% yield), as a white solid after lyophilization. LCMS (M+H)+: 799.1. 1H NMR (DMSO-d6, 500 MHz): δ 12.44 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.99 (m, 1H), 7.98 (s, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 5.89 (d, J=8.5 Hz, 1H), 4.54 (d, J=17.0 Hz, 1H), 4.34 (m, 1H), 4.05 (d, J=17.0 Hz, 1H), 3.93 (s, 3H), 3.76 (m, 4H), 3.70 (m, 4H), 2.40 (s, 3H), 0.62 (d, J=6.5 Hz, 3H). RTA IC50: 11 nM
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:25]=1)[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1.[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38]([N:7]([CH2:6][C:5]1[CH:23]=[C:24]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:25]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:12][CH2:13]1)=[O:39]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1cc(CNC2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(-c2ccncc2)c1
Product: COc1cc(CN(C(=O)c2sc3c(F)ccc(F)c3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(-c2ccncc2)c1

Procedure:
Biaryl amine 243 (18 mg, 42 μmol) is treated with acid chloride 8 (14 mg, 51 μmol) using Method D to afford the title compound.
Reaction SMILES: C=O.[C:3](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:17][C:18]1[CH:48]=[CH:47][C:21]2[N:22]3[C:26]([CH2:27][N:28]([CH:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)[CH2:29][C:20]=2[CH:19]=1)=[N:25][N:24]=[C:23]3[CH:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][C:18]1[CH:48]=[CH:47][C:21]2[N:22]3[C:26]([CH2:27][N:28]([CH:30]4[CH2:34][CH2:33][N:32]([CH3:3])[CH2:31]4)[CH2:29][C:20]=2[CH:19]=1)=[N:25][N:24]=[C:23]3[CH:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:39][CH2:40]1
Reactant: Clc1ccc2c(c1)CN(C1CCNC1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(N2Cc3cc(Cl)ccc3-n3c(nnc3C3CCN(c4ccccn4)CC3)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
Formaldehyde (18 μl, 37 wt. % solution in water, 0.22 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added to a solution of the amine from example 56 (100 mg, 0.22 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution (10 ml) was added, the mixture was stirred vigorously for 10 minutes, and the layers were separated. The organic layer was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol: 0.88 ammonia (95:5:0.5) as eluant. The product was azeotroped with ether to afford the title compound (60 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>CO>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1
Reactant: BrCCCCCBr
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A reaction container was charged with 1,5-dibromopentane (43 g, 186.6 mmol), sodium carbonate (30 g, 280 mmol) and 100 ml of methanol which were weighed and the mixture was stirred at ambient temperature. Then, p-toluidine (10 g, 93.3 mmol) was dissolved in methanol (50 ml) and the solution was added dropwise to the reaction solution. The reaction solution was heated to 55° C. and stirred for 5 hours. The reaction solution was filtered and the resulting filtrate was concentrated under a reduced pressure. The resulting oily mixture was dissolved in ethyl acetate, which was washed with aqueous saturated sodium bicarbonate by using a separating funnel and extracted with 3% hydrochloric acid. Sodium bicarbonate was added to the water phase with stirring the water phase to neutralize it and then the water phase was extracted with ethyl acetate three times. The resulting ethyl acetate solutions were combined and the combined solution was dried using magnesium sulfate and filtered and the filtrate was concentrated under a reduced pressure and distilled under a reduced pressure to obtain 1-(4-methylphenyl)piperidine (8.2 g, yield: 50.3%).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:13]C(C(OC)=O)C=C)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:36][C:37]1([CH3:49])[S:41][C@@H:40]2[C@H:42]([NH2:45])[C:43](=[O:44])[N:39]2[C@H:38]1[C:46]([OH:48])=[O:47]>C(Cl)Cl.C(N(CC)CC)C.CC(N(C)C)=O>[CH3:36][C:37]1([CH3:49])[S:41][C@@H:40]2[C@H:42]([NH:45][C:10]([C@H:9]([NH2:13])[C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[O:12])[C:43](=[O:44])[N:39]2[C@H:38]1[C:46]([OH:48])=[O:47]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: C=CC(NC(C(=O)O)c1ccc(O)cc1)C(=O)OC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [K]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Temperature: 22.5 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
A suspension of the potassium salt of D(-) p-hydroxy-N(1-methoxycarbonyl-2-propenyl)-alpha-aminophenylacetic acid (3.607 g, 1.19 cmoles), methylene chloride (25 ml), dimethylacetamide (2.5 ml) and TMSO (1.82 ml) was stirred at room temperature (20-25° C.) for 45 minutes. Thereafter triethylamine hydrochloride (1.63 g; 1.19 cmoles) was added and after 15 minutes the result was a translucid solution which was cooled to -20° C. Pivalyl chloride (1.45 ml; 1.2 cmoles) in methylene chloride (1.25 ml) and a drop of triethylamine were added. The reaction mixture was stirred for 60 minutes at a temperature of from -10 to -7° C. Thereafter a solution of 6-APA (1 cmole) prepared according to Example 1 was added under the conditions specified in that Example. Then, in a like manner, 3.25 g of amoxicillin (ratio of 1:1,50 with respect to 6-APA) were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: Nc1ccccc1N
Reactant: COc1cccc2c1CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1cccc2c1CCc1cc(Nc3ccccc3N)ccc1C2=O

Procedure:
For the synthesis of the title compound, 0.54 g (0.0020 mol) of 8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.08 g (0.010 mol) of phenylenediamine, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 1.60 g (0.0166 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O. Purification is carried out by column chromatography (flash; SiO2; hexane 80%/ethyl acetate 20%). C22H20N2O2 (Mr=344.42)
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:11][O:12][CH2:13][CH:14]=[CH2:15])([CH2:9][CH3:10])[CH2:7][OH:8])[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O>CS(C)=O>[CH2:13]([O:12][CH2:11][C:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])([CH2:9][CH3:10])[CH:7]=[O:8])[CH:14]=[CH2:15]
Reactant: C=CCOCC(CC)(CO)COCC=C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: C=CCOCC(C=O)(CC)COCC=C

Procedure:
2,2-Bis(allyloxymethyl)-1-butanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.S(O[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CN(C)C=O>[OH:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([O:5][CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:42][CH2:41]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccsc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)c2ccsc2)CC1
Temperature: 100 °C
Yield: 79.2 %

Procedure:
To a stirred solution of 2-hydroxy-2-phenyl-2-(thiophen-3-yl)acetic acid (0.75 g, 3.197 mmol) in toluene (4 mL) and dimethyl formamide (0.4 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (735 μL, 4.919 mmol) was added followed by tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (0.909 g, 2.459 mmol) in toluene (3.5 ml) and dimethyl formamide (0.35 mL). The reaction mixture was heated at 100° C. overnight. After this time, the reaction mixture was cooled to RT and concentrated in vacuo. The crude mixture purified by silica gel column chromatography eluting with a gradient of iso-hexane:ethyl acetate (1:0 to 3:1) to afford the title compound (0.84 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH:4][CH2:13][CH:14]=[O:15]
Reactant: O=CCCl
Reactant: COCc1ccc(C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxymethylaniline )0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([O:17]CC)=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+].[CH2:26]1COC[CH2:27]1>>[CH2:26]([C:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH3:27]
Reactant: C1CCOC1
Reactant: CCOC(=O)C12CC=CCC1COc1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Product: CCc1cccc2c1C1(C(=O)O)CC=CCC1CO2

Procedure:
A solution of the compound from Example 16 (4.4 g, 17 mmol) and potassium trimethylsilanolate (4.36 g, 34 mmol) in 50 ml THF was refluxed for 2 hours. The precipitate was collected by filtration, dissolved in water and acidified with 1N HCl. After further workup, the title compound was obtained as a white solid (3.9 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[NH:6][C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[N:6]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Br)c3c2C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Br)ccc(Cl)c42)CN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 1.67 mmol) in DMF (5 mL), sodium hydride (200 mg, 5.0 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 4.2 mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase HPLC to obtain the 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.39 (s, 1H), 8.12 (d, 1H), 7.66 (d, 1H), 7.26 (d, 1H), 7.1 (d, 1H),4.67 (m, 4H), 3.7 (m, 2H), 3.27 (t, 2H), 3.18 (m, 2H), 3.15 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].CO.O.[C:20](OCC)(=[O:22])C>CO>[Cl:1][C:2]1[N:11]=[C:10]([O:22][CH3:20])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(F)c(OC)nc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 12 mL of methanol, a solution of 1.3 g of 28% sodium methoxide/methanol in 3 mL of methanol was dropped, and the mixture was stirred at room temperature for 40 minutes. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.2 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH:16]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([S:19]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: OC1CNC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(C1CC1)N1CC(O)C1
Reaction time: 16 h

Procedure:
To a solution of azetidin-3-ol hydrochloride (1.00 g, 9.13 mmol) (purchased from Matrix) and N,N-diisopropylethylamine (4.77 mL, 27.4 mmol) in tetrahydrofuran (100 mL) at 0° C. was added cyclopropanesulfonyl chloride (0.930 mL, 9.13 mmol) and the reaction was stirred for 16 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 1N HCl, saturated sodium bicarbonate, and brine, dried over sodium sulfate, decanted and concentrated to afford a yellow oil used without further purification (1.04 g, 64%). 1H NMR (300 MHz, CDCl3): 4.61 (p, 1H), 4.14-4.07 (m, 2H), 3.93-3.86 (m, 2H), 2.69 (br s, 1H), 2.42-2.32 (m, 1H), 1.20-1.11 (m, 2H), 1.06-0.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:20][CH:19]([CH2:21][OH:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:6]=2[CH:17]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:3]2[O:20][CH:19]([C:21]([OH:25])=[O:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:6]=2[CH:17]=1
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A portion (4.5 g) of the 5-chloro-3-(2-chlorophenyl)7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 13 was dissolved in 200 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (4.9 g), water (10 ml) and concentrated sulfuric acid (6.9 g) was added dropwise over time, and the resulting mixture was stirred for 8 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the solution was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 2.6 g of 5-chloro-3-(2-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 220°-221.5° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.