Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(O)cc2)cc1)c1ccccc1

Procedure:
Prepared by treating 1t with boron tribromide (3 eq) in CH2Cl2 at room temperature. Yield (29%); 1H NMR (d6-DMSO) δ 11.95 (br s, 1H), 10.57 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 13H), 6.85 (t, J=8.8 Hz, 4H), 6.38 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 510 (M+H+).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]2[C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C@@H:10]3[CH2:16][O:17][C:5]=2[C:4]=1[O:18][CH3:19].[C:20]([Li])(C)(C)C.CI>O1CCCC1.CCCCCC.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH3:19][O:18][C:4]1[C:5]2[O:17][CH2:16][C@@H:10]3[C@@H:9]([C:6]=2[CH:7]=[CH:8][C:3]=1[CH3:20])[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15]
Reactant: [Li]C(C)(C)C
Reactant: COc1c(Br)ccc2c1OC[C@@H]1[C@@H]2CCCN1C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)ccc2c1OC[C@@H]1[C@@H]2CCCN1C
Reaction time: 0.08 h

Procedure:
To a solution of 2.3 g of trans-8-bromo-7-methoxy-4-methyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine (Example 21) in 45 ml of tetrahydrofuran at -70° is added 5.6 ml of 2.6M t-butyllithium in hexane. After 5 minutes at -70°, 1.36 g of methyl iodide is added. After warming to 0°, the reaction mixture is diluted with ethyl acetate and washed with water. After drying over magnesium sulfate the solvent is removed in vacuo. Acidification of the residue with ethanolic hydrochloric acid yields trans-7-methoxy-4,8-dimethyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 277°-278°.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]1>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:21][CH2:22]1
Reactant: CCOC(=O)CCCN1CCC(c2ccccc2Cl)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1ccccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(2-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH2:10]=[CH:11][C:12]([NH:14][C:15]([CH2:18][OH:19])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:10]=[CH:11][C:12]([NH:14][C:15]([CH2:18][O:19][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[F:7])([F:6])[F:5])([CH3:17])[CH3:16])=[O:13]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C=CC(=O)NC(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CC(=O)NC(C)(C)COC(F)(F)C(F)C(F)(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Hexafluoropropene (13 g, 0.086 mol) was added over 30 minutes to a stirred mixture of CH2═CH(CO)NHC(CH3)2CH2OH (5.0 g, 0.035 mol), acetonitrile (190 mL) and Cs2CO3 (1.0 g, 0.003 mol) at 15-20° C. The resultant light yellow solution was stirred for an additional 1 h, after which TLC analysis (eluting with CH2Cl2 and CH3OH; 17:1 v/v) indicated the reaction was complete. The solution was filtered, and the filtrate concentrated under reduced pressure to give CH2═CHC(O)NHC(CH3)2CH2OCF2CFHCF3 as a light brown liquid (7.5 g ). 19F NMR (CDCl3): δ−75.8 (m, 3F), −79.9 (dm, 1F), −82.8 (dm, 1F), and −212.3 (dm, 1F) ppm; 1H NMR (CDCl3): δ 6.2 (dd, 1H), 6.1 (dd, 1H), 5.6 (dd, 1H), 5.6 (brs, 1H, overlaps), 4.8 (dm, 2H, JHF=44 Hz), 4.2 (dm, 2H), 1.4 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanot/conc. ammonia (700:50: 1) Rf =0.39, FD-MS: M+ =580.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][C:11]2[N:12]=[C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1([C:13]2[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:10]3[CH2:9][NH:8][CH2:29][CH2:28][C:11]=3[N:12]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CNCC3)cc1
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-Pyrrolidin-1-yl-4-p-tolyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.075 g, 0.19 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). After 16 h, the mixture was concentrated, diluted with saturated (satd.) aqueous (aq.) NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Purification by FCC (2 M NH3 in MeOH/CH2Cl2) provided the title compound (0.044 g, 79%). HPLC: Rt=7.7 min. MS (ESI): mass calcd. for C18H22N4, 294.4; m/z found, 295.4 [M+H]+. 1H NMR (CDCl3): 7.42-7.34 (m, 2H), 7.28-7.22 (m, 2H), 3.87 (s, 2H), 3.61-3.58 (m, 4H), 3.20 (t, J=6.2, 2H), 2.82 (t, J=6.2, 2H), 2.39 (s, 3H), 1.97-1.94 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]([CH3:20])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:20][C:11]1[S:10][C:9]([NH:8][C:6]([C:5]2[CH:21]=[CH:22][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=4)[CH2:33][CH2:34]3)=[N:3][CH:4]=2)=[O:7])=[N:13][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1sc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)nc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a mixture of 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide (50 mg, 0.152 mmol) and anhydrous N-methylpyrrolidinone (10 mL) in a sealed tube was added 4-(3-trifluoromethyl-phenyl)-piperidine hydrochloride (80 mg, 0.30 mmol) followed by diisopropylethylamine (0.11 mL, 0.63 mmol). The mixture was heated in an oil bath at 70° C. overnight. After concentration, the crude was purified by RP-HPLC to give 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide as an off-white powder. LCMS calcd for C28H25F3N4OS (m/e) 522, obsd 523 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][OH:13])=[CH:6][CH:5]=1>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#CCO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCCO)cc1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2C=C[C:20]([O:23]C)=[C:19](OC)[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1OC=CC=1)=O.C(OP(CC#[N:54])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[O:23][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]#[N:54])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: COc1ccc(C(=O)c2ccco2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccco2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)furane (0.87 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3 M) with a reaction time of 3 hours at room temperature. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.78 g (76%) of a mixture of the E and Z isomers as an off white solid: mp 78-82° C.; 1H NMR (CDCl3) δ 7.68-7.73 (m, 2 H), 7.16-6.75 (m, 7 H), 6.54-6.39 (m, 3 H), 5.87 (s, 1 H), 5.30 (s, 1 H), 3.93 (s, 3 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.88 (s, 3 H); 13C NMR (CDCl3) δ 152.0, 150.7, 150.5, 150.4, 149.3, 148.8, 148.7, 148.7, 145.2, 145.0, 129.6, 126.7, 122.1, 121.6, 118.1, 118.0, 116.5, 115.6, 112.5, 112.1, 112.0, 111.5, 110.9, 110.8, 90.5, 90.2, 55.9, 55.9, 55.9, 55.8; Anal. Calcd for C15H13NO3. Theoretical: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.61; H, 5.09; N, 5,18.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:14]>O1CCCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CI
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)cc21
Yield: 97.4 %

Procedure:
Sodium hydride (4.10 g of a 60% dispersion in paraffin wax) was added to a stirred solution of 6-bromoindole (10 g, 51.3 mmol) in tetrahydrofuran (100 ml) at 0° C. under a nitrogen atmosphere. After 1 hour iodomethane (6.38 ml. 102.6 mmol) was added and the cooling bath removed. After 12 hours methanol was added dropwise until effervescence ceased and then the solvent was removed in vacuo. The thick residue was diluted with dichloromethane and washed first with water then with brine. The organic layer was dried (magnesium sulphate) and concentrated in vacuo to give a dark yellow oil. Filtration through a plug of silica with 90% hexane/10% ethyl acetate as eluant gave the subtitle compound as a pale yellow oil (10.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[Cl:21][C:11]([C:10]1[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=1)[CH2:7][S:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])=[O:12]
Reactant: COC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid (61.6 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (5 mL). This was followed by dropwise addition of oxalyl dichloride (121.76 mg, 0.96 mmol, 4.00 equiv) with stirring at room temperature. Then a few drops of N,N-dimethylformamide were added as catalyst. The resulting solution was heated to reflux for 30 min. The resulting mixture was concentrated under vacuum to yield 60 mg (crude) of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as yellow oil. The crude was used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:11]=[C:7]([C:8]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:9])[CH:6]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)N3CCOCC3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with morpholine there was obtained N-[3-(2,3-dihydroxy-propoxy)-2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4 methylsulphanyl-benzenesulphonamide as a white foam.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])(=[O:20])=[O:19]
Reactant: CCCCOC(=O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
27.8 g (0.2 mol) of n-butyl hydroxyacetate (95% pure by GC) and 20.2 g (0.2 mol) of triethylamine are first introduced into 300 ml of dichloromethane at -5° C. 34.4 g (0.3 mol) of methanesulfonyl chloride in 50 ml of dichloromethane are slowly added dropwise at 0° to 5° C. Stirring of the batch at 0° C. is continued overnight, ice water is added, the phases are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried, and the solvent is removed on a rotary evaporator leaving a colorless oil which is subjected to incipient distillation in vacuo. n-Butyl methylsulfonyloxyacetate is isolated as an almost colorless oil (40.5 g, 96.3% of theory, GC content 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:27])=[CH:8][CH:9]=1)=[O:24]
Reactant: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2N)cn1

Procedure:
N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-nitro-benzamide (301 mg, 0.7 mmol) was dissolved in 95% ethanol (4 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 50 mg) and subjected to a hydrogen atmosphere (40 psi) for 2 hours. The catalyst was removed by filtration and the solvents were removed in vacuo. The product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z): 353/355 (M+H)+; C19H16N3O2Cl requires 353.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(O)c(N)c1
Reaction time: 72 h
Yield: 83 %

Procedure:
A mixture of 4-methoxy-2-nitrophenol (30.2 g, 0.18 mol), 10% Pd/C, ethanol (200 mL), and ethyl acetate (200 mL) was hydrogenated at ambient pressure and temperature for three days before it was filtered and concentrated in vacuo to give the title compound as a dark brown solid (20.78 g): 1H NMR (CDCl3, 200 MHz): δ=6.64 (m, 1H), 6.32 (m, 1H), 6.21 (m, 1H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[O:14][CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)c(I)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(C)c(C#N)c1I
Temperature: 60 °C
Yield: 89.4 %

Procedure:
The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (50.0 mL) and the potassium carbonate (4.6 g, 33 mmol) and ethyl iodide (2.1 mL, 33 mmol) were added. The reaction was heated to 60° C. and monitored by LC/MS. After heating for 2 hrs the reaction was complete. This was allowed to cool, diluted with ethyl acetate (300 mL) and filtered to remove the remaining solids. The organic layer was washed with water (3×), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark solid. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-ethoxy-2-iodo-6-methylbenzonitrile as a pale yellow crystalline solid (5.0 g, 96%). LCMS calculated for C12H13INO2 (M+H)+: m/z=329.9; found: 330.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12](C2C=COC=2C=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=CC=C(O)C=1C(OC)=O>>[C:40]([O:39][C:37]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2C=O)c1OS(=O)(=O)c1ccc(C)cc1
Agent: COC(=O)c1c(N)cccc1O
Product: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)cccc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:34]=[C:33](B(O)O)[CH:32]=[CH:31][CH:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:28])[N:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Cc1cccc(B(O)O)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1cccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 6-methylpyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.868 min, m/z=449.2; 1H NMR (CD3OD) 1.28 (m, 1H), 1.56 (d, 3H), 1.61 (m, 1H), 1.95 (m, 2H), 2.23 (m, 1H), 2.34 (m, 1H), 2.46 (m, 1H), 2.55 (s, 3H), 3.11 (m, 1H), 3.46 (m, 2H), 5.50 (m, 1H), 7.06 (m, 4H), 7.19 (d, 1H), 7.31 (m, 2H), 7.51 (d, 1H), 7.73 (m, 3H).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([OH:14])([C:10]([F:13])([F:12])[F:11])=[O:9].[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22](C1CCCCO1)[N:21]=[C:20]2[C:32]1[N:37]=[C:36]([O:38][C@H:39]2[CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43][C:40]32[CH2:42][CH2:41]3)[CH:35]=[N:34][CH:33]=1)#[N:16]>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[C:8]([OH:14])=[O:9].[CH2:42]1[C:40]2([CH2:43][CH2:44][NH:45][CH2:46][C@@H:39]2[O:38][C:36]2[N:37]=[C:32]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([C:15]#[N:16])[CH:18]=4)[NH:22][N:21]=3)[CH:33]=[N:34][CH:35]=2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)n2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.3 %

Procedure:
Triethylsilane (0.075 mL, 0.468 mmol) and TFA (1.0 mL, 12.98 mmol) were sequentially added to a solution of (4R)-tert-butyl 4-(6-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (99.4 mg, 0.187 mmol) in CH2Cl2 (1.0 mL) and the resulting solution was stirred at 25° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (3.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-1H-indazole-5-carbonitrile 2,2,2-trifluoroacetate (63.2 mg, 0.137 mmol, 73% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (1 H, s), 8.99 (1 H, d, J=11.2 Hz), 8.71 (1 H, s), 8.65 (1 H, d, J=8.2 Hz), 8.35 (1 H, s), 7.86 (1 H, d, J=8.7 Hz), 7.79 (1 H, dd, J=8.6, 1.4 Hz), 5.00 (1 H, s), 3.75 (1 H, d, J=12.9 Hz), 3.47 (1 H, t, J=12.0 Hz), 3.34 (1 H, d, J=12.7 Hz), 3.10-3.22 (1 H, m), 2.37-2.47 (1 H, m), 1.17 (1 H, d, J=14.5 Hz), 0.78-0.90 (2 H, m), 0.61-0.69 (1 H, m), 0.55 (1 H, dd, J=8.7, 4.2 Hz). 19F NMR (377 MHz, DMSO-d6) δ ppm −73.67 (3 F, s). MS (ESI, pos. ion) m/z: 347.1 (M+1).
Reaction SMILES: C(=O)([O-])O.[Na+:5].[C:6]([OH:17])(=[O:16])[CH2:7][CH2:8][S:9][S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>O>[C:6]([O-:17])(=[O:16])[CH2:7][CH2:8][S:9][S:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[Na+:5].[Na+:5]
Reactant: O=C(O)CCSSCCC(=O)O
Agent: *CC(*)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCSSCCC(=O)[O-]

Procedure:
A 1-liter polypropylene beaker was charged with a solution of 42 g (0.50 mole) of sodium hydrogen carbonate in 100 g of distilled water, followed by the slow addition of 52.5 g (0.25 mole) of 3,3′-dithiodipropionic acid, which required about 10 minutes. The resulting paste was spread on an evaporating tray and dried. The salt product was white-colored and melted above 225° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: NCCCc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCCc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
1-(para-fluorophenyl)-3-aminopropane (1.00 g, 6.53 mmol, 1 eq.) and triethylamine (0.91 mL, 6.53 mmol, 1 eq.) were dissoved in THF (10 mL) at 25° C. under N2. Then a THF solution (5 mL) of acetyl chloride (0.46 mL, 6.53 mmol, 1 eq.) was added dropwise via an addition funnel over 10 minutes. Worked up after 20 minutes by filtering off the solids then stripping the filtrate to obtain an amber oil. The oil was purified over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 1.10 g of an amber oil as product. MS (ESI) detects (M+H)+=196.