Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:16][CH:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(SCc2ccccc2)nc1
Reaction time: 2 h

Procedure:
A solution of phenylmethanethiol (1 ml, 8 mmol) in N,N-dimethylformamide (15 ml) under an atmosphere of argon was treated with sodium hydride (352 mg, 8.8 mmol, 60% dispersion in oil). After stirring at room temperature for 15 minutes a solution of 5-bromo-2-chloropyridine (1.84 g, 9.6 mmol) in N,N-dimethylformamide (5 ml) was added. After 2 hours, water and ethyl acetate were added. The organic layer was separated and washed with water, brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was then purified by chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound. MS (ES+) 280/282 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:47])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl[S:56]([N:59]=C=O)(=[O:58])=[O:57].CC(O)(C)C>C(Cl)Cl.CO.C(Cl)Cl>[Cl:47][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]=1[N:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][N:14]2[C:11]3[CH2:12][CH2:13][N:8]([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:9][C:10]=3[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[N:15]2)[CH2:31][CH2:32]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3NS(C)(=O)=O)CC2)C1
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(Cl)c1N1CCN(CCCn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(N)(=O)=O)C3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 97 mg (0.14 mmol) of 1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 3 mL of CH2Cl2 was treated with 1.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. To this crude material in 0.5 mL of CH2Cl2 was added dropwise a premixed solution of chlorosulfonyl isocyanate (18 μL, 0.209 mmol) and 2-methyl-2-propanol (20 μL, 0.209 mmol) in CH2Cl2 (0.150 mL). The reaction mixture was allowed to stir at 25° C. overnight. Preparative TLC (silica, 2-10% MeOH/CH2Cl2) provided the title compound (84 mg, 78%). TLC (silica, 10% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C32H41ClF3N7O6S2, 775.22; m/z found, 776.2 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH:33]=O)=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH2:33][NH:1][C@@H:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=4[CH:17]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.8 %

Procedure:
6-[(4S)-4-Amino-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (330 mg, 1.21 mmol) and 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (Reference Example 8; 281 mg, 1.21 mmol) were dissolved in N,N-dimethylformamide (8.8 ml). Sodium sulfate (1.4 g) was added to this solution and the mixture was stirred at room temperature for 5.5 hours. Sodium triacetoxyborohydride (386 mg, 1.82 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 2 days. After completion of the reaction, dichloromethane and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction solution and the organic layer was separated. The organic layer was washed with water (3×) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by flash column chromatography (chloroform/methanol) to yield 324 mg (58%) of the title compound in the form of light brown foamy crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[N:21]=1)[C:16](Cl)=[O:17].Cl.CCCCCC.C(OC(=O)C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:13]([Cl:12])[CH:14]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(Cl)n1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccc(F)cc2)cc(Cl)n1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
1.75 g (0.01 mol) of 4-fluorobenzenesulfonamide were dissolved in 30 ml of pyridine, and added dropwise by 2.06 g (0.01 mol) of 2-chloro-6-methoxyisonicotinoyl chloride at 0° C. to 5° C., followed by agitation for 2 hrs. at room temperature. After acidified by adding aqueous hydrochloric acid, the precipitate was extracted by ethyl acetate. The organic layer obtained was dried and them concentrated to precipitate crude crystals, which were recrystallized by n-hexane/ethylacetate to 2.1 g (yield: 61.0%) of N-(4-fluorophenylsulfonyl)-2-chloro-6-methoxy isonicotinamide as white crystal.
Reaction SMILES: C(OC([N:8]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([C:29]([O:31][CH3:32])=[O:30])[C:18]2=[O:33])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([CH2:34][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[CH:20]=[C:19]([C:29]([O:31][CH3:32])=[O:30])[C:18]4=[O:33])[CH2:13][CH2:14]3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: COC(=O)c1cc2ccc(OC)cc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2ccc(OC)cc2n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1=O
Reaction time: 3 h
Yield: 85 %

Procedure:
To 2 mL of a chloroform solution containing 0.31 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, 1 mL of trifluoroacetic acid was added and stirred for 3 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.22 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a colorless oil.
Reaction SMILES: C([C:3]([N:9]=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:6][C:7]#[N:8])[C:4]#[N:5])C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:8][C:7]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: CCC(C#N)(CC#N)N=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
To a solution of ethyl 2-(phenyldiazenyl)succinonitrile (Preparation 55, 2.84 g, 15.43 mmol) in dichloromethane (103 mL) was added a 10% aqueous solution of potassium carbonate (77 mL, 55.71 mmol). The reaction was stirred at room temperature for 18 hours. The organic layer was separated dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-3% MeOH in DCM to afford the title compound (1.24 g, 44%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1I)[CH:2]=[CH:3][CH3:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CCCCCC>[CH2:3]([C:2]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[N:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH:1]=1)[CH3:4]
Reactant: CC=CCOCc1c(I)ccnc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC1=COCc2c1ccnc2OC
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A 3-liter 3-necked round-bottom flask is equipped with a heating mantle monitored by a J-KEM thermocouple and an overhead stirrer; under nitrogen, the flask is charged with 3-(but-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine (30.0 g, 93.9 mmol), as prepared in example 2, and 939 mL (0.1M) of N,N-dimethylformamide, followed by successive addition of anhydrous potassium carbonate (26.0 g, 188 mmol), palladium(II) acetate (422 mg, 1.88 mmol) and tetrabutylammonium chloride (13.1 g, 47.0 mmol). The light brown mixture is brought to 90° C. and stirred for 30 min. The now dark brown mixture is allowed to cool to 85° C. and stirring is continued for 20 h when TLC (10% EtOAc/hexane) indicates complete reaction. After being cooled to ambient temperature, the mixture is filtered through Celite 545® (80 g), washed with MTBE (0.5 L) and the filtrate is poured into 800 mL of ice water and extracted with MTBE (3×600 mL). The combined extracts are successively washed with water (700 mL) and brine (700 mL), dried over anhydrous Na2SO4 (150 g). Evaporation in vacuo yields crude 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine 1H NMR (400 MHz) indicates an endo/exo ratio of 8:1. Vacuum distillation at, ca. 112°-120° C. yields 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine as an 11:1 endo/exo mixture. 1H-NMR (400 MHz, CDCl3) δ8.04 (d, J=5.4 Hz, 1H), 6.65 (d, J=5.4 Hz, 1H), 6.54 (s, 1H), 5.04 (s, 2H), 3.94 (s, 3H), 2.32 (m, 2H), 0.97 (t, J=7.2 Hz, 3H), HRMS (EI+): calc for C11H13NO2 : 191.0946, Found: 191.0952. IR 3450, 2962, 1731, 1602, 1581, 1454, 1390, 1362, 1313, 1267 cm-1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:10]2[O:11][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2ccccc2)c2oc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccccc2)c2oc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a stirred solution of 100 mg (0.42 mmol) 4-methoxy-7-phenyl-benzooxazol-2-ylamine, 0.087 ml (0.62 mmol) triethylamine and 5.1 mg N,N-dimethyl-4-aminopyridine in 5 ml THF at room temperature was added dropwise a solution of 0.064 ml (0.54 mmol) 4-fluoro-benzoyl chloride in 2 ml THF and stirring continued at 65° C. for 16 h. The reaction mixture was then concentrated in vacuo. To the residue was added water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4 then 4/1 ethyl acetate/hexane) followed by trituration in ether afforded 50 mg (33%) 4-fluoro-N-(4-methoxy-7-phenyl-benzooxazol-2-yl)-benzamide as a light yellow crystalline solid. EI-MS m/e (%): 362 (M+, 90), 123 ([FC6H4CO+, 100).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>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]>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:17]([CH3:18])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(=O)c1ccccc1
Reactant: COc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cccc(C(C)C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 54.1 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (13.8 mg, 0.015 mmol) and sodium t-butoxide (125 mg, 1.3 mmol). The tube was capped with the septum, and purged with argon. Toluene (2 mL) was added and the mixture stirred for 1 min at room temperature. 3-Bromoanisole (0.125 mL, 1.0 mmol) and propiophenone (0.16 mL, 1.2 mmol) were added to the tube. The mixture was heated to 80° C. and stirred until the starting halide had been completely consumed, as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 130 mg (54%) of α-(3-methoxyphenyl)propiophenone. 1H NMR (CDCl3, 300 MHz) 7.93-7.90 (m, 2H), 7.45-7.14 (m, 4H), 6.85-6.68 (m, 3H), 4.61 (q, J=6.9 Hz, 1H), 3.72 (s, 3H), 1.49 (d, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[F:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]2([OH:85])[CH2:84][CH2:83][CH2:82][CH2:81]2)=[C:74]([CH3:86])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52].C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]4([OH:85])[CH2:81][CH2:82][CH2:83][CH2:84]4)=[C:74]([CH3:86])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:7][C:6]=1[F:12]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
(4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 47 mg, 0.230 mmol), toluene (2.5 mL), palladium acetate (3.4 mg, 0.015 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (12.6 mg, 0.031 mmol), potassium phosphate (97 mg, 0.459 mmol) and water (0.250 mL) were added to 1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol (Example 33-(3); 75 mg, 0.153 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for two hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound (24 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Yield: 98.1 %

Procedure:
Treatment of ((2R)-7-chloro-8-(2-chlorophenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (2.13 g, 4.62 mmol) in ethanol (100 mL) and ethyl acetate (15 mL) with platinum (IV) oxide (84% Pt, 0.50 g) according to the procedure described for Example 69, Step 8 provided 2.10 g (96%) of ((2R)-7-chloro-8-(2-chlorophenyl)chroman-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nccn1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
148 g (936 mmol) of 1-benzyl-1H-imidazole are suspended in 480 ml of acetonitrile and, at −20° C., 120 ml (87.1 g; 860 mmol) of triethylamine are added. Over a period of 15 minutes, 211.2 ml (239 g; 2208 mmol) of ethyl chloroformate are then added dropwise. The reaction mixture is stirred at −20° C. for 10 minutes. After warming to 15 to 20° C., the reaction mixture is stirred for 18 h and then concentrated in vacuo. Water, a saturated sodium chloride solution and a saturated sodium bicarbonate solution are added to the residue, and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution and, after drying with magnesium sulfate, concentrated in vacuo. The residue is subjected to a fractional distillation under high vacuum (boiling point=173 to 181° C., pressure=1.7 to 1.2 mbar).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN
Solvent: O
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
2,4-Difluoro-1-nitrobenzene (25.0 g, 157 mmol) was stirred and thereto was added dropwise 40% aqueous methylamine solution (38.4 g) at 0° C. over not less than 15 min. After the completion of the dropwise addition, the mixture was continuously stirred at the same temperature for 1.5 hr. Water (500 mL) was added to the reaction mixture, and the resulting solid was collected by filtration to give the title compound (26.4 g, 99%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:64][C@H:65]([NH2:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:72][C@H:65]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH3:64])[CH:12]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1cc(-n2nc(Cl)c3ccccc32)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](Nc1cc(-n2nc(Cl)c3ccccc32)ccn1)c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 3-chloro-1-(2-chloro-pyridin-4-yl)-1H-indazole (0.29 g, 1.1 mmol) in toluene (6 mL) under nitrogen were added palladium acetate (0.025 g, 0.11 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.069 g, 0.1 mmol), and (S)-(−)-α-methylbenzylamine (0.18 mL, 1.38 mmol), followed by sodium t-butoxide (0.3 g, 3.1 mmol). The resulting mixture was heated at 70° C. for 1 h, during which TLC and HPLC indicated completion of reaction. After cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate and brine and dried over MgSO4. Flash chromatography of the crude product mixture with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-hexane gave the title compound as a tan colored solid. MS (ES+): 349.3 [M+H]+, 347.1 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: OCCCO
Reactant: COc1ccc(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 5-bromo-2-methoxybenzaldehyde (52.3 g, 243 mmol), 1,3-propanediol (30 ml, 31.6 g, 415 mmol), and 4-toluenesulphonic acid (0.3 g) in toluene (350 ml) was heated to reflux in a Dean-Stark apparatus for 20 h. The mixture was cooled to RT, washed with saturated NaHCO3 solution (100 ml), then the organic layer was separated and combined with a CH2Cl2 solution (100 ml). The extract was washed (brine; 50 ml), dried (Na2SO4), and concentrated in vacuo to give a brown oil (66.2 g). The crude product was distilled to afford the title compound (58.2 g) as a colourless viscous oil b.p. 115-120° C., 0.02 mmHg δH (80 MHz; CDCl3) 1.2-1.5 (1H, br m, CH2CHHCH2), 1.9-2.4 (1H, m, CH2CHHCH2), 3.78 (3H, s, OMe), 3.6-4.4 (4H, m, CH2CH2CH2), 5.76 (1H, s, OCH), 6.67 (1H, d, J 8.8 Hz, ArH ortho to OMe), 7.33 (1H, dd, J 8.8, 2.3 Hz, ArH para to acetal), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to acetal); m/z (El) 274 (44%), 273 (31), 272 (45), 271 (27), 216 (34), 215 (47), 214 (35), 213 (44), 193 (34), 135 (22), and 87 (100).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 198.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.82 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=464.1 [M+H]+.