Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31]O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:52]([NH2:63])(=[O:62])[C:53]1[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:55](N)=[O:56]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][N:63]2[C:52](=[O:62])[C:53]3[C:54](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:55]2=[O:56])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NCCN2C(=O)c4ccccc4C2=O)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
To a stirred solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (0.6 g), from Synthetic Example 22, in THF (14.3 mL), under Argon, was added sequentially triphenylphosphine (1.08 g, 4.13 mmol), phthalamide (0.21 g, 1.45 mmol), followed by diisopropyl azadicarboxylate (DIAD, 0.31 g, 1.52 mmol) dropwise over 30 minutes. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried and concentrated. The residue was partially purified by chromatography on silica gel, followed by preparative reverse phase HPLC to give 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-indazole-1-carboxylic acid tert-butyl ester (131 mg) which was used directly in the next step.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:30])=S.[Na+].[Na+].O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S([O-])([O-])=S
Reactant: CCCCCCOc1ccc(Sc2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 883.8 %

Procedure:
In 100 g of acetic acid was dissolved 15 g of (4-hexyloxyphenyl) phenyl sulfide obtained in Synthesis Example 1-21. While the solution was maintained at an internal temperature of 30° C., 5.1 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1.3 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 100 g of methylene chloride and 20 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 14 g of the target compound, (4-hexyloxyphenyl) phenyl sulfoxide as amorphous solid. Yield 95%.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20](CC([Cl:26])=O)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].[C:27](O)([C:29](F)(F)F)=[O:28]>>[ClH:26].[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([CH:4]([N+:5]([CH3:8])([CH3:6])[CH3:7])[C:3]([C:27](=[O:28])[CH3:29])([CH2:9][C:10](=[O:11])[O-:12])[OH:2])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Cc1ccc(CC(=O)Cl)cc1
Agent: Cl
Product: CC(=O)C(O)(CC(=O)[O-])C(c1ccc(CC(C)C)cc1)[N+](C)(C)C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
5.5 g (0.028 moles) of carnitine hydrochloride are dissolved in 9 mls of CF3COOH, and to the solution an excess (20 mls) of p-isobutylphenyl acetyl chloride is added and the mixture is kept under stirring at 40°-45° C. for 4-5 hours. At the end of this period of time the mixture is partitioned with H2O--CHCl3, the organic phase is discarded and the aqueous phase is concentrated at reduced pressure at a bath temperature of about 50° C. A gelatinous raw material is obtained which is crystallized with isopropanol, the precipitate thus obtained is filtered, rapidly washed with ether because of its hygroscopicity, and dried under vacuum at a temperature not exceeding 50° C.; 6.8 g of a product are obtained (yield 65%) having the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH:10]([OH:11])[Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5][CH:4]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC1=CCC(CCO)=CC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC1=CCC(CC(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)=CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The crude compound (1) was dissolved in N,N-dimethylformamide (150 mL) and treated at room temperature with imidazole (44.8 g, 658 mmol) and t-butyldiphenylsilyl chloride (85.6 mL, 329 mmol). The resulting solution was stirred at room temperature for 2 d (reaction was essentially complete after a few hours) after which time it was diluted with 10% ethyl acetate in hexane, washed 3× with water, dried over anhydrous MgSO4, filtered and evaporated to give crude 1-methoxy-4-[2-(t-butyldiphenylsilyl)hydroxyethyl]-cyclohexa-1,4-diene (3). The mixture, which was contaminated with the over-reduced product 4-[2-(t-butyldiphenylsilyl)hydroxyethyl]-cyclohex-1-ene (4), was used in the next step without further purification. Compound (3): 1H NMR (CDCl3) δ 1.07 (9H, s), 2.25 (2H, t, J=6.0 Hz), 2.70 (4H, s), 3.55 (3H, s), 3.77 (2H, t, J=6.0 Hz), 4.62 (1H, br s), 5.43 (1H, br s), 7.22-7.93 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of ethyl (2E)-3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)acrylate (0.86 g, 0.0025 mol) in ethyl acetate (10 mL, 0.1 mol) was added palladium (600 mg, 0.006 mol). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 h. The reaction solution was filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (40% ethyl acetate/hexane) to give the desired product as a white solid (609 mg, 70%). LCMS for C14H14ClFN3O4(M+H)+: m/z=342.1.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[C@@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21].Cl.O1CCOCC1>O>[CH3:16][C@@:10]12[C:13]([CH3:14])([CH3:15])[C@@H:7]([C:6]3[C:4](=[O:5])[N:20]([CH2:19][C:18]([F:23])([F:22])[F:17])[NH:21][C:11]=31)[CH2:8][CH2:9]2
Reactant: CCOC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Temperature: 100 °C
Yield: 17 %

Procedure:
A mixture of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (Intermediate 4; 5.00 g, 22.3 mmol) and 2,2,2-trifluoroethylhydrazine (70% in water; Aldrich; 25.00 g, 153 mmol) was heated in a sealed tube at 100° C. for 19 h. The reaction mixture was allowed to cool, and HCl in dioxane (4 M; 40 mL, 160 mmol) was added cautiously. The reaction mixture was heated again at 100° C. for 45 min, cooled to room temperature, and added to water (200 mL). The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, evaporated, purified by flash chromatography (20-50% ethyl acetate) to give (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.04 g, 17%) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:42])=[O:41]
Reactant: COc1cc(C(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
30.0 g (63.8 mmole) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 500 ml of methylene chloride. 11.5 ml (83.0 mmole) of triethylamine and 5.93 ml (76.6 mmole) of methanesulfonyl chloride were then added, in that order, to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was then diluted with methylene chloride and washed with 1 N aqueous hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 1:9 by volume as the eluent, to give 34.8 g of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[SH:13][C:14]1[CH:15]=[C:16]([C:20]2([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)[CH:3]=2)[NH:8]1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cccc(Sc3ccc4[nH]c(=O)ccc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
6-Iodo-1H-quinolin-2-one (5.13 g, 18.9 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (5f, 4.57 g, 20.8 mmol) were dissolved in 1,4-dioxane (160 mL) and degassed for 10 minutes with N2. iPr2NEt (6.6 mL, 37.9 mmol) was added, followed by Pd2dba3 (434 mg, 0.47 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (548 mg, 0.95 mmol), and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was filtered and concentrated, and the residue was purified by silica gel chromatography (0-100% MeOH in EtOAc) to give the desired product, 5g.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:42][CH2:43][CH3:44])[C:34]=1[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:46]1[C:50]([C:51]2[CH:52]=[C:53]3[C:63](=[CH:64][CH:65]=2)[O:62][C:56]2([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][C:54]3=[O:66])=[N:49][N:48]=[N:47]1>O.CN(C=O)C.CCN(CC)CC>[CH2:43]([O:42][C:33]1[CH:32]=[C:28]([C:29]([N:59]2[CH2:60][CH2:61][C:56]3([CH2:55][C:54](=[O:66])[C:53]4[C:63](=[CH:64][CH:65]=[C:51]([C:50]5[NH:49][N:48]=[N:47][N:46]=5)[CH:52]=4)[O:62]3)[CH2:57][CH2:58]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=1)[CH3:44]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccnc(F)c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (290 μL), HOBT (160 mg) and WSC hydrochloride (200 mg) were added to a DMF (8 mL) solution of 3,5-diethoxy-4-(2-fluoropyridin-4-yl)benzoic acid (266 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (325 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=4.0 Hz), 8.25-8.20 (2H, m), 7.32 (1H, d, J=8.0 Hz), 7.29-7.26 (1H, m), 7.10 (1H, s), 6.76 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.98 (2H, s), 2.10-1.75 (4H, m), 1.17 (6H, t, J=8.0 Hz). MS [M+H]+=573.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([S:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=3[F:36])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][S:27][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:16])=[O:15])[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=1
Reactant: CCOc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio]-6-ethoxy-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step ii) (0.24 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was evaporated, the residue was azeotroped with DCM (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid. Yield: 0.18 g
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1C=CC=CC=1>[CH2:14]([O:13][P:12]([Cl:27])([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]2[C:1]1=[O:25])=[O:16])[CH3:15]
Reactant: CCOP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOP(=O)(Cl)CCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of (6-phthalimidohexyl)phosphonic acid, diethyl ester, benzene, and phosphorus pentachloride is refluxed according to the procedure of Example 1(f) to give ethoxy(6-phthalimidohexyl)phosphinyl chloride.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1(=[N:34]O)[C:33]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH2:23][CH2:22][CH2:21]1.[OH2:36]>ClCCl>[O:36]=[C:20]1[NH:34][C:33]2[CH:32]=[CH:31][C:30]3[C:25]([C:24]=2[CH2:23][CH2:22][CH2:21]1)=[CH:26][CH:27]=[CH:28][CH:29]=3
Reactant: ON=C1CCCc2c1ccc1ccccc21
Reactant: O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: O=C1CCCc2c(ccc3ccccc23)N1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of methanesulfonic acid (25 ml) and phosphorus pentaoxide (5.2 g, 37 mmol) was heated at 90° C. for 3.5 h. The solution was cooled to 50° C. and 3,4-dihydro-2H-phenanthren-1-one-oxime (4.8 g, 23 mmol) was added. The solution was heated at 60° C. for 10 minutes and then at 80° C. for 3.5 hr. The hot reaction mixture was added to a mixture of ice (300 g) and water (100 ml). The precipitated solid was isolated by filtration, redissolved in dichloromethane (50 ml), dried (MgSO4) and evaporated in vacuo to afford a white product. Purification was achieved using column chromatography with silica gel (200 g) and a mixture of heptane and ethyl acetate (1:2) to afford 4.8 g of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[C:16](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (Matrix Scientific, 1 g) was dissolved in methanol and cooled in an ice-bath under a nitrogen atmosphere. Thionyl chloride (5 mL) was added slowly. The reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (75 mL and water (100 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford 1.0 g of product.
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>O1CCCC1>[CH2:11]([NH:14][C:15]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:16])[CH:12]=[CH2:13]
Reactant: C=CCN=C=S
Reactant: CC(C)(C)C1=CCNCC1
Solvent: C1CCOC1
Product: C=CCNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 20 ml. of anhydrous tetrahydrofuran there is dissolved 5.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine, and with stirring there is added 3.5 grams of allylisothiocyanate in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 24 hours at room temperature and the tetrahydrofuran is evaporated in vacuo. The resulting solid is dried at 50°C/20 mmHg. to remove any unreacted allylisothiocyanate to give N-allyl-4-t-butyl-1,2,3,6- -tetrahydro-1-pyridinethiocarboxamide.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][CH2:45][CH2:46][NH2:47]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: COCCNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 2-methoxyethanamine
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18]([O:20]CC)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23].C1COCC1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([OH:20])=[O:19])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a mixture of ethyl 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (108.9 mg, 0.342 mmol) in a mixture of MeOH (2 mL)/THF (2 mL) at r.t. under N2 was added sodium hydroxide (1.0 mL, 1.0 mmol) (1 M aq.). The mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled to r.t., added with 1.5 ml 1N HCl, and then added 10 ml H2O. The white precipitates were filtered and washed with 3×2 ml H2O and dried (73 mg). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, 2H), 7.25 (t overlapping with dd, 2H), 7.24 (dd, 1H), 7.02 (t, J=8.39, 1H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=291.01, HPLC Rt=1.478 min.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:14][C:8]4[CH:7]=[C:6]5[C:11](=[CH:10][CH:9]=4)[NH:12][C:13]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]5=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc2[nH]c3c(c2c1)CCCC3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]c3c(c2c1)CCCC3)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2,3,4,9-Tetrahydro-1 H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 70° C. The solvent was evaporated and the crude product was then purified on 40 g of silica gel utilizing a gradient of 5-50% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]-dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS m/z calc. 374.2, found 375.3(M+1)+. Retention time of 3.43 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.52(s, 1H), 8.39(s, 1H), 7.46(d, J=1.8 Hz, 1H), 7.10-6.89(m, 5H), 6.03(s, 2H), 2.68-2.65(m, 2H), 2.56-2.54(m, 2H), 1.82-1.77(m, 4H), 1.41-1.34(m, 2H), 1.04-0.97(m, 2H).