Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cc(O)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)ccc2oc1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
DIEA (46.5 μL, 0.27 mmol) was added to 6-hydroxy-3-carboxy-coumarin (50.0 mg, 0.24 mmol) and HATU (101.4 mg, 0.27 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.8 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 81.1 mg of product in 85% yield: LCMS (ESI) m/z 398 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:14]([Li])(CC)C.C1CCCCC1.IC>COCCOC>[CH3:14][C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][C:9]=1[C:11]([OH:13])=[O:12]
Reactant: [Li]C(C)CC
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Solvent: COCCOC
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To a round bottom flask equipped with magnetic stirring, an addition funnel and a nitrogen inlet, was added benzo(1,4)dioxan-6-carboxylic acid (18.00 g, 99.91 mmol) and 1,2-dimethoxyethane (667 mL). This mixture was cooled to −75° C. in a dry ice-acetone bath. To this was added 1.3 M sec-butyl lithium in cyclohexane (230.6 mL, 299.7 mmol) over 1 hour, maintaining reaction temperature below −60° C. The reaction was removed from the cooling bath, allowed to warm to −20° C., and subsequently stirred at −20° C. for 45 min. The reaction was cooled to −50° C., and iodomethane (15.6 mL, 249.8 mmol) was added. The reaction was again removed from the cooling bath, allowed to warm to −20° C., and stirred at this temperature for 45 min. All cooling was removed and the reaction stirred at room temperature for 16 hours. The reaction was quenched by addition of a few mls of 1N HCl (aq) and the solvent removed by evaporation. The residue was made substantially acidic by the addition of aqueous 1N HCl. The resultant precipitate was filtered and washed with water to give a light brown solid, 5-methyl-benzo(1,4)dioxan-6-carboxylic acid, (6.60 g, 33.9 mmol) in 34% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.62 (d, 1H), 6.8 (d, 1H), 4.30 (br s, 4H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([Li])(CC)C.[I:18]I>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[I:18]
Reactant: II
Reactant: COC(=O)Nc1cccc(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(F)c1I

Procedure:
The starting material (3-fluoro-2-iodo-phenyl)-carbamic acid methyl ester was prepared from (3-fluoro-phenyl)-carbamic acid methyl ester by double deprotonation with sec.butyllithium in tetrahydrofuran at −78° C. followed by reaction with iodine. m.p.:80-82° C.
Reaction SMILES: CC1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30](CC(OCC)=O)C3C=CC=CC=3)[C:22]=2[CH:43]=1)#[N:17].[OH-].[NH4+]>O1CCCC1>[NH2:30][C@H:23]1[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]([CH3:27])([CH3:28])[C@@H:24]1[OH:29]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Agent: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](N)[C@H]1O
Temperature: 75 °C

Procedure:
To a solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile ((2.5 g, 12.4 mmol, the title A compound of Example 3) in tetrahydrofuran in a re-sealable tube was added concentrated ammonium hydroxide (2 mL). The tube was sealed and the solution was heated on an oil bath at 75° C. overnight. The resultant solution was cooled to room temperature, concentrated and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to yield the title compound as an oil.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[N:48][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:50][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:48][C:49]([N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-amino-6-morpholinopyridine as the aniline component. (26%, MS=542.3 (M+H))
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=O.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH:3]([OH:2])[CH3:8])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CC(O)CC(=O)O
Agent: Cl
Product: CC(O)CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 29.7 %

Procedure:
Proceeding as in Example 1, but substituting 3-hydroxybutanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 118, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-hydroxybutanoyl)pyrrolidine-2-carboxamide (8.5 mg, 29.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.93 (s, 1H), 7.55-7.60 (m, 2H), 7.28-7.35 (m, 2H), 7.17-7.24 (m, 5H), 6.94-7.02 (m, 4H), 4.67 (m, 1H), 4.47-4.50 (m, 1H), 3.90 (m, 1H), 3.68-3.70 (m, 1H), 3.25-3.30 (m, 1H), 2.63-2.73 (m, 3H), 2.35-2.47 (m, 1H), 2.70-2.30 (m, 1H), 1.86-1.96 (m, 2H), 1.01-1.13 (m, 3H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cl)nc1

Procedure:
Alternatively, 2-chloro-5-nitropyridine can be prepared using the procedure described in the Journal Chemical Society 9 (1941), starting with 2-aminopyrimidine. Nitration of 2-aminopyridine gives 2-amino-5-nitropyridine, which can be converted into 2-hydroxy-5-nitropyridine by a diazonium reaction. Subsequent heating of 2-hydroxy-5-nitropyridine in a phosphorous pentachloride/phosphorous oxychloride mixture yields 2-chloro-5-nitropyridine. The synthesis is summarized below: ##STR13##
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:40]1([CH2:43]Br)[CH2:42][CH2:41]1.[Cl-].[NH4+]>CN(C)C=O>[CH:40]1([CH2:43][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:42][CH2:41]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3CC2CC2)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
A suspension of 0.15 g (0.28 mmol) [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 14 mg (0.32 mmol; 55% dispersion in mineral oil) sodium hydride in 2 mL N,N-dimethyl-formamide was stirred 20 min. at 70° C. 34 μL (48 mg, 0.35 mmol) cyclopropylmethyl bromide were added and the solution was stirred another 45 min. at 70° C. After cooling to room temperature, the mixture was poured into 10% aqueous ammonium chloride solution and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed three times with water, brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with dichloromethane:methanol (9:1 v/v) as eluant to give 0.15 g (91%) of the desired compound as colorless foam. MS (ISP): 585.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]([CH2:25][CH2:26]Cl)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)(C)C>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([N:1]1[CH2:26][CH2:25][N:23]([CH3:24])[CH2:22][CH2:21]1)[CH:14]=3
Reactant: CN(CCCl)CCCl
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide 470B (250 mg, 0.822 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride, Mechlorethamine HCl (316 mg, 1.644 mmol) and sodium carbonate (436 mg, 4.11 mmol) were mixed in t-BuOH (5 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated at 80° C. for 16 hrs in an oil bath. 6 ml of DMF was added to the mixture and the mixture was heated in microwave at 160° C. for 1 hr. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 387.04 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][N:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:8]=2[N:9]=[C:10](Cl)[CH:11]=1)=[O:5])C.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15](/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][N:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:8]=3[N:9]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Yield: 78.9 %

Procedure:
To a solution of 6-chloro-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.8 g, 6.80 mmol) in dioxane (60 ml) were added 4-hydroxyphenylboronic acid (1.03 g, 7.48 mmol) and an aqueous solution of cesium carbonate (0.4M, 30 mL). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.71 g, 0.61 mmol) was then added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, methylene chloride and water were added, and the mixture was acidified until pH=2. The organic layer was washed with water and the aqueous phase was extracted using methylene chloride. The resulting organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.37 g, 79%) as a yellow solid which was used without any further purification.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@H:11]([CH3:39])[O:12][C:13]1[CH:14]=[C:15]([CH:25]=[C:26]([O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[CH:33]=[CH:32]3)[CH:27]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=1)=[O:17])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>CO>[OH:9][CH2:10][C@H:11]([CH3:39])[O:12][C:13]1[CH:14]=[C:15]([CH:25]=[C:26]([O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[CH:33]=[CH:32]3)[CH:27]=1)[C:16]([NH:18][C:19]1[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=1)=[O:17]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc3c(ccn3C)c2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(ccn3C)c2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
10% Hydrochloric acid (0.5 mL) was added to a solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[(1-methyl-1H-indol-5-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (120 mg, 0.22 mmol) in methanol (5 mL). The reaction was stirred at ambient temperature for 1 hour, saturated sodium bicarbonate solution added and the methanol evaporated. The aqueous residue was taken to pH 2 and extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 1% methanol in ethyl acetate, to give the desired product (85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:31])[N:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([O:17][C:32](=[O:34])[CH3:33])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:31])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](O)Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1
Agent: CN(C)c1ccncc1
Product: CC[C@@H](Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1)OC(C)=O
Temperature: 25 °C

Procedure:
N,N-Dimethyl-4-pyridinamine (0.1222 g, 0.001 mol) was added to a solution of intermediate D7 (9.117 g, 0.020 mol) in acetyl acetate (378 ml). The reaction mixture was stirred at reflux for 30 minutes. Subsequently, the mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was redissolved in CH2Cl2. This organic solution was washed with a saturated sodium bicarbonate solution, washed with brine, and was subsequently dried (MgSO4), filtered and the solvent was evaporated in vacuo. The obtained yellow oil was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 3 mobile phases was applied. Phase A: a 0.25% NH4HCO3 solution in water; phase B: methanol; phase C: CH3CN). The desired fractions were collected. The solvent was evaporated and co-evaporated with methanol. The product was crystallized from DIPE/heptane. The white crystals were filtered off and dried in vacuo. Yield: 3.677 g of intermediate D8 (37%; 5-enantiomer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([O:20]C)[N:14]=[C:13]([O:22]C)[N:12]=2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:9]([C:11]1[NH:12][C:13](=[O:22])[NH:14][C:15](=[O:20])[C:16]=1[CH:17]([CH3:18])[CH3:19])=[O:10]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Cl)c2)n1
Agent: Cl
Product: Cc1cc(Cl)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
(3-Chloro-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methanone (49) (3.4 g, 10 mmol) was refluxed with concentrated HCl (35 ml) for 4 hr. After cooling to room temperature, the white precipitate was collected by filtration, washed with cold water and hexane, and dried in high vacuo to afford 3 g (97%) of a white solid. m.p. 254-255° C.; 1H NMR (200 MHz, CDCl3/CD3OD) δ: 1.17 (6H, d, J=6.9 Hz), 2.25-2.45 (4H, m), 7.50-7.71 (3H, m); HRMS (EI): Calc. 306.077120, Found 306.076851.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]2[CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:11]2=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:1]([N:9]1[CH2:13][CH:12]2[CH2:14][S:15](=[O:30])[CH:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[C:11]2[NH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(c1cccnc1)N1CC2CSc3ccccc3C2=N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CC2CS(=O)C3C=CC=CC3=C2N1
Yield: 50.7 %

Procedure:
To a solution of 2-nicotinoyl-3,3a-dihydro-2H,4H-[1]-benzothiopyrano[4,3-c]pyrazole (6 g) synthesized in Example 37, dissolved in dichloromethane (50 ml) was added m-chloroperbenzoic acid (2.5 g, purity: 70%) with ice-cooling, to give rise to a reaction. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:chloroform=1/40) to obtain 2.3 g of a title compound (yield: 73%).
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C@H:45]2[CH2:50][CH2:49][C@@H:48]([C:51]([F:54])([F:53])[F:52])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C@H:45]3[CH2:50][CH2:49][C@@H:48]([C:51]([F:54])([F:53])[F:52])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with cis-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamide, the title compound was obtained as colorless solid (0.12 g, 24%): 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (d, J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H), 3.34 (s, 3H), 2.36-2.28 (m, 1H), 2.13-1.97 (m, 2H), 1.74-1.56 (m, 8H), 0.91-0.85 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 438.1 (M+1); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5](N)[CH:6]=[CH:7][CH:8]=1.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[BrH:22]>O>[Br:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: Br
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
3-Methoxy-2-nitro-phenylamine (360 mg, 2.14 mmol) was dissolved in HBr (48%, 4.8 mL) at 0° C. A solution of sodium nitrite (0.16 g, 2.40 mmol) in water (360 μL) was added dropwise to the stirred solution over one hour period while the temperature was maintained at 0° C. Then a cold (0° C.) freshly prepared solution of CuBr2 (from CuSO4.5H2O (1.0 g) and HBr (48%, 1.0 mL) mixed 30 min. at room temperature to give a dark purple solution) was added at 0° C. to the reaction mixture. The resulting solution was stirred at 0° C. for 3 hours and at room temperature for 2 days. The reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 482 mg (2.08 mmol, 97%) of 1-bromo-3-methoxy-2-nitrobenzene as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C:23]=1[Cl:24])[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>C(OCC)(=O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([C:23]=1[Cl:24])[C:20]([C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(Br)c(Cl)c1C(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,4,5-trimethoxytoluene (0.83 g; 4.6 mmol), 4C (4.6 mmol), aluminium chloride (0.62 g, 4.6 mmol) and dichloromethane (20 ml) is stirred at room temperature for 3 hours. A mixture of water and ethyl acetate (1:1 v/v; 50 ml) is then added. The organic phase is concentrated and the residue is crystallized from diisopropylether and recrystallized from methanol. The solid material is collected by vacuum filtration, washed with water and dried yielding yellow crystals, 0.7 g, (35.4%) mp 87-88° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.CC(C)C(C1CCCCC1=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cu]I.C(OCC)(=O)C>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1
Reactant: Ic1cnccn1
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H](Nc2cnccn2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of CuI (0.006 g, 0.030 mmol), benzyl N-[(1S,3R)-3-aminocyclo-hexyl]carbamate, 18e, (0.075 g, 0.302 mmol) and cesium carbonate (0.197 g, 0.604 mmol) in DMF was evacuated and refilled with nitrogen multiple times. 2-iodopyrazine (0.036 mL, 0.362 mmol) and 2-(2-methylpropanoyl)cyclohexanone (0.020 mL g, 0.121 mmol) were then added and the reaction was stirred at room temperature overnight. The reaction was diluted into ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 40 mg of the desired product as yellow solid.