Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].[OH-].[Na+]>I>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccncc1F
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccncc1F
Temperature: 140 °C
Reaction time: 5 h

Procedure:
2-(3-Fluoro-pyridin-4-yl)-propan-2-ol (from the previous step, 6.40 g, 41.3 mmol) was dissolved in 50 mL of 57% HI aqueous solution. Red phosphorus (4.48 g, 144.0 mmol) was added and the mixture was stirred at 140° C. for 5 hours. The reaction mixture was cooled to room temperature, neutralized with 5N aq NaOH and extracted with ether. The combined organic layers were washed with H2O and brine, then dried over Na2SO4 and concentrated under vacuum. The title compound was obtained by distillation. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.27 (d, J=7.04 Hz, 6 H), 3.25 (hept, J=7.04 Hz, 1 H), 7.21 (dd, J=5.44 Hz, 1 H), 8.33-8.36 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].N.C1C[N:25]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([C:18]([NH2:25])=[O:20])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: Cn1cc(C(N)=O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
The product of step A (234 mg) was dissolved in dichloromethane (5 mL) and ethanolic ammonia (2 M, 2.0 mL, 4.0 mmol): PyBOP (579 mg, 1.10 mmol) was added in one portion and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with acetic acid (ca. 0.5 mL), diluted with ethyl acetate (40 mL) and washed with water (2×10 mL) and saturated brine (10 mL). The organics were dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel. Elution with dichloromethane-methanol (4:1) afforded 4-(3,4-Dichloro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid amide (28 mg, 12% yield) as a dark yellow-colored solid. An analytical sample was prepared by crystallization from methanol: m.p. >250° C.; 1H NMR (DMSO-d6, 400 MHz) δ10.38 (s, 1H), 8.30 (s, 1H), 7.85 (br s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.45 (br s, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 5.70 (s, 1H), 3.33 (s, 3H). Anal. Calcd./Found for C13H11Cl2N3O2: C, 50.02/50.02; H, 3.55/3.19; N, 13.46/13.21.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][NH2:13].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N.O>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:12][NH2:13])=[CH:4][CH:3]=1
Reactant: NCCCl
Reactant: Cc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(SCCN)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 4-methylbenzenethiol (1.24 g), 2-chloroethylamine HCl (2.3 g) and Cs2CO3 (5.3 g) in CH3CN (30 mL) was stirred at 50° C. for 2 days. To the reaction mixture were added EtOAc (50 mL) and H2O (30 mL). The organic phase was separated, washed with H2O (2×30 mL) and concentrated under reduced pressure to give product 24. Yield: 1.67 g, 95%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: O=C1COc2ccc(I)cc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3cc(I)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-iodo-3(2H)-benzofuranone (0.551 g, 2.12 mmol) [Cagniant, P. et al. Hebd. Seances Acad. Sci., Ser. C, 1976, 282 (21), 993-6] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 0.480 g (58%) of the title compound as a tan solid: mp 169° C.(dec) which was used without further purification.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH2:5][CH2:6]Br.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1.CCCCCCC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:16]#[N:17])[CH2:6][CH2:5][CH2:4]2)=[CH:11][CH:10]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: N#CC1(c2ccc(Br)cc2)CCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of potassium hydroxide (56.5 g) and tetrabutylammonium bromide (2.92 g) in toluene (400 mL) and water (30 mL) was warmed to 70° C. Then, 1,3-dibromopropane (39.0 g) and 2-(4-bromophenyl)acetonitrile (35.5 g) were sequentially added thereto, and the mixture was stirred at 100° C. for 3 hours. After the reaction mixture was cooled to 80° C., heptane (100 mL) was added thereto, and the mixture was further cooled to room temperature. The reaction mixture was filtered and washed with hexane, and the organic layer was separated. The obtained organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (24.0 g, yield: 56%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([NH:30][C:28]([NH:27][C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)([C:5]2[CH:4]=[CH:3][C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:7][N:6]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C1COCCN1
Reactant: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(N2CCOCC2)cn1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
1-(1-(5-Bromopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea (64 mg, 0. 12 mmol), morpholine (1.3 eq), Pd2(dba)3 (0.2 eq), Xantphos (0.6 eq) and Na—O-t-Bu (3.2 eq) were stirred in toluene (0.5 mL) at room temperature. The reaction mixture was purged with N2 several times and then was heated at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature, and Et2O was added. The resulting solution was washed with H2O, brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was purified by chromatography (silica gel, hexanes/EtOAc) to give 1-cyclopentyl-3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-morpholinopyridin-2-yl)-2-phenylethyl)urea (39 mg, yield: 60.9%). LC-MS ESI 557.28 (M+H) (10-90% MeOH in H2O with 0.1% TFA in a 4-min run, retention time=3.63 min); 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (d, J=2.9 Hz, 1 H), 7.57 (s, 1 H), 7.40 (d, J=10.0 Hz, 1 H), 7.28 (s, 1 H), 7.24-7.17 (m, 2 H), 7.14 (d, J=7.3 Hz, 1 H), 7.09 (t, J=7.5 Hz, 2 H), 7.02 (d, J=8.8 Hz, 1 H), 6.66 (d, J=7.6 Hz, 2 H), 4.48 (d, J=12.5 Hz, 1 H), 4.34 (d, J=7.1 Hz, 1 H), 4.00-3.91 (m, 1 H), 3.90-3.87 (m, 4 H), 3.56 (d, J=12.5 Hz, 1 H), 3.18 (m, 4 H), 2.09-2.01 (m, 1 H), 1.92-1.83 (m, 1 H), 1.68-1.57(m, 4 H), 1.49-1.40 (m, 1H), 1.32-1.24 (m, 1 H).
Reaction SMILES: Cl.Cl.[C@H]1(CN2CCC(N[C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH:65][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[C:29]([O:32][CH2:33][C:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[O:36][CH:35]=2)[CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(OCc4coc5ccccc45)cccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 307.5 %

Procedure:
To a ice-cold solution of 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (105, see example 50) (200 mg, 0.651 mmol) in 2 ml of dimethylformamide is added Huenigs base (334 ul, 1.95 mmol). After stirring at 0° C. for 10 min, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.651 mmol) and PyBOP (356 mg, 0.684 mmol) are added subsequently. The mixture is stirred at room temperature over night. It is then diluted with ethyl acetate, washed with 1N-NaOH and brine, dried over anhydrous sodium sulphate and evaporated to give 980 mg of a lightbrown oil. The crude material is purified by chromatography on silicagel using cyclohexane and ethylacetate (1:1).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:59][CH3:60])[N:32]2[CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45](C(OCC2C=CC=CC=2)=O)[CH2:44]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:59][CH3:60])[N:32]2[CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate.
Reaction SMILES: O.C(O)(=O)C(O)=O.[CH:8]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]([C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26]3)=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.C1C2CCC3C=CC=CC=3N(C(C3CCCN(CC4C=CC=CC=4)C3)=O)C=2C=CC=1.C(O)(=O)C(O)=O.Br[CH2:75][C:76]([O:78][CH2:79][CH3:80])=[O:77].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:79]([O:78][C:76](=[O:77])[CH2:75][N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([CH2:23][N:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:18]=3[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]2=3)[CH2:26]1)[CH3:80]
Reactant: CCOC(=O)CBr
Reactant: O=C(C1CCCN(Cc2ccccc2)C1)N1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCCC(CN2c3ccccc3CCc3ccccc32)C1
Reaction time: 7 h
Yield: 86.8 %

Procedure:
A mixture of the above piperidine (2.05 g, 7 mmol), ethyl bromoacetate (1.36 g, 8.1 mmol), potassium carbonate (1.7 g, 12.3 mmol) and acetone (50 ml) was heated at reflux temperature under stirring for 7 h. The mixture was filtered and the solvent evaporated in vacuo. The oily residue was purified on silica gel (20 g) using ethyl acetate as eluent to give 2.3 g (87%) 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)-1-piperidylacetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:2][C:3]#[CH:4].[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16]O[CH2:14]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]12[O:11][CH2:12][C:13]([CH2:17][CH2:18][CH3:19])([CH2:16][O:10]1)[CH2:14][O:9]2)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: C#CCCOCCC12OCC(CCC)(CO1)CO2

Procedure:
1-[2-(But-3-ynyloxy)ethyl]-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(but-3-ynyloxy)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using the methodology outlined in Example I.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:20]([CH:21](O)[CH3:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:9]1[C:20]([CH:21]([CH3:22])[C:5]#[N:6])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCc1nn2ccc3c(c2c1C(C)O)CCO3
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCc1nn2ccc3c(c2c1C(C)C#N)CCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Under an argon atmosphere, to a solution of boron trifluoride diethyl ether complex (0.411 mL, 3.24 mmol) and trimethylsilyl cyanide (0.576 mL, 4.32 mmol) in chlorobenzene (10 mL) was added a solution of 1-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanol (250 mg, 1.08 mmol) in chlorobenzene (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (195 mg, yield 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.CC1(C)C(C)(C)OB([C:45]2[CH:57]=[CH:56][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:47][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[C:2]([C:45]2[CH:46]=[CH:47][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[CH:56][CH:57]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3-6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 5 h. After cooling, the reaction mixture was diluted with water, and the product was extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford tert-butyl 4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)(methyl)amino)piperidine-1-carboxylate
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:24])[CH3:23])[N:15]=3)=[CH:12][N:13]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:23])[CH3:24])[N:15]=3)=[CH:12][N:13]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:2]
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCC(O)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.8 %

Procedure:
To a solution of 2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenol (30 mg, 85 μmol) in iPrOH (4 mL), 3M aq. NaOH (1 mL) followed by (S)-3-chloro-propane-1,2-diol (67 μL, 0.85 mmol) is added. The reaction mixture is stirred at rt for 15 h, and is then diluted with EtOAc and washed with 1M aq. NaOH followed by brine. The org. solution is dried over Na2SO4, filtered and evaporated to give 3-{2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenoxy}-propane-1,2-diol (9 mg) as a yellow solid; LC-MS: tR=0.79 min, [M+H]+=426.80.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.[CH3:27][S:28]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C@H:34]([C:50](O)=[O:51])[CH2:33]1)(=[O:30])=[O:29]>C(#N)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:50]([C@@H:34]2[CH2:33][C@@H:32]([O:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:36][N:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[O:51])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
1.11 g of 1-(2-hydroxyethyl)piperazine, 1.29 ml of diethyl cyanophosphonate and 1.18 ml of triethylamine were added, in that order, whilst ice-cooling, to a solution of 3.00 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline [prepared as described in step 54(a)(i) above] in 35 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 2.60 g of the title compound, as a powder.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:16]2[CH:17]=[CH:18][C:19]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Reactant: Brc1ccc(I)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Temperature: 100 °C
Yield: 44 %

Procedure:
A mixture of 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (Compound 14) (5.0 g, 13.5 mmol), 4-bromoiodobenzene (10.76 g, 38 mmol), Pd(PPh3)4 (0.5 g, 0.43 mmol) and potassium carbonate (K2CO3)(5.52 g, 40 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 100° C. overnight, then worked up with ethyl acetate/brine. The organic phase was collected, dried over Na2SO4, and purified by flash column (hexanes to hexane/ethyl acetate 90:1). The main fraction was collected, concentrated, and a precipitate was filtered to give a white solid (Compound 15) (2.35 g, in 44% yield). Confirmed by LCMS (APCI): calculated for C24H17BrN (M+H): 398; Found: 398.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(OCC)(=O)C.[ClH:22]>CO.O1CCOCC1.[Pd]>[ClH:22].[ClH:22].[CH3:1][N:2]([CH3:15])[S:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)Nc1ccc(C#N)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1ccc(CN)cn1

Procedure:
A solution of 6-(dimethylaminosulfonylamino)-3-cyanopyridine (250 mg, 1.1 mmol) in a mixture of MeOH (25 mL) and 4 N HCl in dioxane (1 mL) was hydrogenated over 10% Pd/C catalyst using a continuous flow hydrogenation apparatus (conditions: flow rate 1.0 mL/minute, 25° C., 1 atmosphere). The reaction was monitored by TLC (ethyl acetate). The methanol was concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16].[Cl-]>C(=S)=S>[CH3:6][C:7]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([C:3](=[O:4])[CH2:2][Br:1])=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: O=C(Cl)CBr
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)C(=O)Nc2cc(C(=O)CBr)ccc21

Procedure:
bromoacetyl chloride (9.76 g) is added dropwise to a stirred mixture of 3,3-dimethyloxindole (5 g) and aluninum chloride (10.33 g) in carbon disulfide (100 ml). The reaction mixture is stirred at reflux overnight and cooled. The solvent is decanted, and a mixture of ice and water poured into the residue. Methylene chloride is added to the mixture, which is filtered. The filtrate is separated, the aqueous layer is extracted with methylene chloride and the combined organic extracts are washed with sat'd aqueous sodium bicarbonate, dried, filtered, concentrated, and recrystallized from boiling isopropanol, affording the desired product, M.P.=230°-232° C.