Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([NH:29][C:30](=[O:52])[C@@H:31]([NH:44]C(=O)OC(C)(C)C)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)[CH:14]=[C:15]([C:17]#[C:18][C:19]3[C:24]([F:25])=[C:23]([F:26])[N:22]=[C:21]([F:27])[C:20]=3[F:28])[CH:16]=2)[C:5]([F:53])=[C:4]([F:54])[N:3]=1.FC(F)(F)C(O)=O>>[NH2:44][C@@H:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[C:30]([NH:29][C:13]1[CH:12]=[C:11]([C:10]#[C:9][C:6]2[C:5]([F:53])=[C:4]([F:54])[N:3]=[C:2]([F:1])[C:7]=2[F:8])[CH:16]=[C:15]([C:17]#[C:18][C:19]2[C:20]([F:28])=[C:21]([F:27])[N:22]=[C:23]([F:26])[C:24]=2[F:25])[CH:14]=1)=[O:52]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(C#Cc2c(F)c(F)nc(F)c2F)cc(C#Cc2c(F)c(F)nc(F)c2F)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](N)C(=O)Nc1cc(C#Cc2c(F)c(F)nc(F)c2F)cc(C#Cc2c(F)c(F)nc(F)c2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-di-tert-butyl (6-((3,5-bis((perfluoropyridin-4-yl)ethynyl)phenyl)amino)-6-oxohexane-1,5-diyl)dicarbamate (0.02 g, 0.04 mmol) was reacted with neat trifluoroacetic acid (TFA) (2 mL) and the solution was stirred for 4 hours at room temperature. TFA was evaporated and the product (25 mg, 96%) was purified by recrystallization with ethanol: 1H-NMR (400 MHz, CD3OD) δ 8.08 (d, J=1.3 Hz, 2H), 7.66 (t, J=1.3 Hz, 1H), 4.10 (t, J=6.5 Hz, 1H), 2.96 (t, J=15.3 Hz, 2H), 1.94-2.10 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[O:6][C@H:5]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:34])[CH2:16][CH2:17][C@@:18]45[CH2:24][C@:23]64[CH2:25][CH2:26][C@H:27]([OH:33])[C@:28]([C:30]([OH:32])=[O:31])([CH3:29])[C@@H:22]6[CH2:21][CH2:20][C@H:19]5[C@:14]3([CH3:35])[CH2:13][CH2:12]2)[CH3:10])[CH2:4][CH:3]=1.[N+](=[CH2:38])=[N-]>>[CH3:1][C:2]1[C:7](=[O:8])[O:6][C@H:5]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:34])[CH2:16][CH2:17][C@@:18]45[CH2:24][C@:23]64[CH2:25][CH2:26][C@H:27]([OH:33])[C@:28]([C:30]([O:32][CH3:38])=[O:31])([CH3:29])[C@@H:22]6[CH2:21][CH2:20][C@H:19]5[C@:14]3([CH3:35])[CH2:13][CH2:12]2)[CH3:10])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@@H]([C@@H](C)[C@H]2CC[C@@]3(C)[C@@H]4CC[C@H]5[C@](C)(C(=O)O)[C@@H](O)CC[C@@]56C[C@@]46CC[C@]23C)OC1=O
Reactant: C=[N+]=[N-]
Product: COC(=O)[C@]1(C)[C@@H](O)CC[C@]23C[C@]24CC[C@]2(C)[C@@H]([C@H](C)[C@@H]5CC=C(C)C(=O)O5)CC[C@@]2(C)[C@@H]4CC[C@@H]13

Procedure:
Abrusogenin [10 mg] was methylated in ethereal diazomethane at room temperature overnight. On work-up, abrusogenin methyl ester [8 mg] was obtained as colorless prisms, after recrystallization in EtOAc, and was shown to be pure by tic in solvents 3 (Rf 0.71), 5 (Rf 0.56), and 6 (Rf 0.60). This derivative exhibited the following data: mp 246°-248°; [α]D +31.2° (c 0.08, CHCl3 -MeOH, 1:1); uv, (EtOH) end absorption; ir, νmax (KBr) 3529 (OH), 1710 (C=O), 1258, 1135, 1060, 1018 cm-1, 1H nmr, (360 MHz, CDCl3) δ 6.61 (1H, m, H-24), 4.50 (1H, dd, J=13.4 Hz, J=2.8 Hz, H-22), 4.10 (1H, dd, J=11.3 Hz, J=44 Hz, H-3), 3.71 (3H, s, 29-Ome), 2.57 (1H, m, H-23a), 1.91 (3H, br. s, 27-Me), 1.15 (3H, s, 30-Me), 1.00 (3H, d, J=6.8 Hz, 21-Me), 0.96 (3H, s, 18-Me), 0.93 (3H, s, 28-Me), 0.61, 0.39 (2H, d, J=4.2 Hz, 19-H2) ppm; 13C nmr, (90.8 MHz, CDCl3) δ 177.42 (s, C-29), 166.56 (s, C-26), 139.65 (d, C-24), 128.12 (s, C-25), 80.21 (d, C-22), 75.32 (d, C-3), 54.80 (s, C-4) 51.85 (q, 29-CH3), 48.79 (s, C-14), 47.85 (d, C-8), 47.42 (d, C-17), 45.20 (s, C-13), 44.30 (d, C-5), 40.05 (d, C-20), 35.40 (t, C-12), 32.58 (t, C-15), 31.43 (t, C-1), 29.88 (t, C-19), C-2), 27.85 (t, C-23), 27.55 (t, C-7), 26.32 (t, C-11), 25.52 (t, C-16), 25.04 (s, C-10), 23.07 (t, C-6), 19.91 (s, C-9), 19.38 (q, C-28), 17.86 (q, C-18), 17.14 (q, C-27), 12.82 (q, C-21), 9.26 (q, C-30) ppm; ei-ms, (70 ev) m/z 498 (M+, 1%), 480 (M+ -OH, 3), 465 (1), 448 (4), 421 (1), 367 (3), 314 (22), 299 (6), 247 (11), 215 (14), 199 (11), 173 (30), 147 (42), 133 (55), 119 (60), 111 (68), 107 (76), 105 (68), 95 (100) 81(72), 67 (39), 55 (48).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][OH:2])=[CH:6][C:7]=1[F:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of (4-benzyloxy-3-fluoro-phenyl)-acetic acid methyl ester (7.1 g, 25.7 mmol) in ether (150 mL), was LAH (1.07 g, 28.3 mmol) added portionwise at 0° C. The reaction mixture stirred for 2 hours at the same temperature. The reaction was quenched with H2O (5 mL) at 0° C. The solid material was filtrated off and washed with ether (50 mL). The ether was dried over MgSO4 and concentrated under vacuum to afford the desired compound (5.2 g, 82%) as a white solid. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.34-7.48 (m, 5H), 7.09-7.17 (m, 2H), 6.96-6.98 (m, 1H), 5.17 (s, 2H), 4.66 (s, 1H), 3.60 (b, 2H), 2.68 (m, 2H). LCMS 246.3 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Reactant: Oc1n[nH]c2ccccc12
Product: CNc1ccc(C)cc1C(=O)n1nc(O)c2ccccc21
Yield: 40.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-methylisatoic anhydride according to the general procedue A above and afforded the desired amine as yellow solid in 40.5% yield; m.p. 173°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[SH:9].[CH2:10](Cl)[C:11](=[CH2:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][CH:11]([CH2:13][S:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:12]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(C)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(SCC(C)C)c1
Yield: 88.5 %

Procedure:
A 100-ml eggplant type flask was charged with 6.9 g (50 mmol) of 2,5-dimethylthiophenol, 5.5 g (60 mmol, 1.2 equivalents) of methallyl chloride which was a halogenated olefin, 6.9 g (50 mmol, 1 equivalent) of potassium carbonate and 30 ml of acetone, and the mixture was refluxed under heat for 1 hour. The reaction mixture was allowed to cool, insolubles were removed by filtration, and the acetone was distilled off. The resultant residue was re-dispersed in n-hexane and washed with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give 8.6 g (yield 89%) of 2-methyl-3-(2,5-dimethylphenylthio)propane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:29])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2cc(Br)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2cc(Br)ccc21
Temperature: 25 °C
Yield: 119.4 %

Procedure:
A solution of (R)-2-(7-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80 g, 244 mmol) and Lawesson's reagent (59.1 g, 146 mmol) in toluene (900 mL) was heated at reflux for 3 h then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(7-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (60 g, 71%) as a yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.20 (s, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.70 (m, 1H), 4.99-4.88 (m, 2H), 4.23-4.15 (m, 2H), 1.57 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H). SFC (Table 1, Method 30) Rt=2.902 min.; [α]D20=20.79 (C=0.002 g/mL in methanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[C:11]([NH:12][S:23]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)(=[O:25])=[O:24])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cc1nsc2cc(Cl)c(N)cc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2cc3c(C)nsc3cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-3-methyl-benzo[d]isothiazol-5-ylamine (46 mg) in pyridine (0.26 mL), was added a solution of 3,4-dimethoxybenzenesulfonyl chloride (35 mg) in pyridine (0.26 mL). The resulting reaction mixture was stirred at RT under nitrogen overnight. The reaction mixture was then diluted with EA, washed well with HCl 1M (pH˜2-3), the organic phase was washed with water, brine, dried (MgSO4), filtered and concentrated to yield the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]([CH3:13])([CH3:12])[C:8](=[N:10][OH:11])[NH2:9])=[O:5])[CH3:3].[CH2:15](OC(OCC)OCC)C>CC(O)=O>[O:11]1[CH:15]=[N:9][C:8]([C:7]([NH:6][S:4]([C:2]([CH3:14])([CH3:1])[CH3:3])=[O:5])([CH3:13])[CH3:12])=[N:10]1
Reactant: CC(C)(NS(=O)C(C)(C)C)C(N)=NO
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(NS(=O)C(C)(C)C)c1ncon1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (1.0 g, 4.5 mmol) in triethoxymethane (7.5 ml, 45 mmol) was treated with AcOH (7.5 ml) at rt. The reaction was allowed to stir at rt for 16 h. The reaction was then concentrated to dryness azeotroping with toluene 3×. The resulting yellow oil was purified on silica gel (Biotage, EtOAc/hexanes gradient) to give the expected product N-(2-(1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (750 mg, 3.24 mmol, 72% yield) consistent by LCMS and NMR. LC-MS retention time: 0.987 min; m/z (MH+): 232. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 5.54 (s, 1H), 1.65 (s, 3H), 1.59 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C([F:44])C=2)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:44])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2cccc(F)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-6-(3-fluorophenylthiomethyl)-2-methoxybenzoate (Intermediate 103).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11].[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[C:10]([C:23]1[CH:24]=[CH:25][C:20]([O:26][CH3:27])=[CH:21][CH:22]=1)=[O:11]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.5 %

Procedure:
Anhydrous AlCl3 (260 mg, 2 mmol) was added to a well-stirred solution of 3,4,5-trimethoxybenzoyl chloride (25) (461 mg, 2 mmol) and anisole (216 mg, 2 mmol) at 0° C. in CH2Cl2 (25 mL). The mixture was stirred while allowing it to warm to room temperature. After 6 h, the resultant dark reaction mixture was poured into ice cold 5% HCl (20 mL), and the CH2Cl2 layer was separated. The aqueous layer was extracted with an additional 30 mL of CH2Cl2, and the combined CH2Cl2 solutions were washed with saturated sodium bicarbonate solution. Evaporation of solvents from the dried CH2Cl2 extract and purification of the residue by chromatography on a column of silica gel, using 5% EtOAc in hexane as eluent, gave product 27 (487 mg, 80%); mp 72°-73° C.; 1H NMR (CDCl3, 200 MHz) δ7.83 (d, J=8.7 Hz, 2H), 7.03 (s, 2H), 6.98 (d, J=8.7 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.88 (s, 6H); CIMS (isobutane) m/e 303 (MH+, 100). Anal. (C17H18O5), C, H.
Reaction SMILES: Cl.[CH:2]1([NH:8][CH:9]2[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.O>[Br:18][CH2:19][C:20]([N:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH:9]1[CH2:11][CH2:10]1)=[O:21]
Reactant: C1CCC(NC2CC2)CC1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To an ice cooled mixture of 1.054 g (6 mmol) of N-cyclohexyl-N-cyclopropylamine hydrochloride, 2.07 g (15 mmol) of potassium carbonate in 15 ml of methylene chloride and 15 ml of water was added 1.2 g (6 mmol) of bromoacetyl bromide. Then the reaction mixture was stirred at RT for 20 h. The organic phase washed with water, dried over sodium sulphate and evaporated to dryness to give 1.33 g of crude compound. Flash chromatography using DCM as eluant afforded 1.12 g of the desiderated compound as colorless oil.
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CNC(SC)=C(C#N)C#N)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 15 g (57.8 mmol) of 2-cyano-3-(4-methoxy-benzylamino)-3-methylmercapto-acrylonitrile, 3.03 ml (61.1 mmol) of hydrazine hydrate and 40 ml of methanol is stirred for 1 hour at RT, heated under reflux for 2 hours and then concentrated by evaporation in vacuo. Recystallization of the residue from ethanol/hexane yields the title compound; m.p. 148-149° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: C1=COCCC1
Reactant: COC(=O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)OC1CCCCO1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Methyl (R)-(+)-lactate (25.0 g) was dissolved in dichloromethane (250 ml), to which was added, under ice-cooling, p-toluenesulfonic acid.hydrate (456 mg). To the mixture was then added dropwise 3,4-dihydro-2H-pyran (24.2 g) during 30 minutes, which was stirred for one hour under ice-cooling. To the reaction mixture was added a 5% aqueous solution of sodium hydrogen carbonate (50 ml), and the mixture was stirred vigorously, followed by separating the organic layer. The organic layer was further washed with a 5% aqueous solution of sodium hydrogen carbonate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave methyl (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate (42.7 g) as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH-:12].[Na+]>>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Product: Oc1cccc(C(F)(F)F)n1
Temperature: 150 °C
Yield: 79.7 %

Procedure:
2-Chloro-6-trifluoromethylpyridine (8.05 g at 98% strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100 psi. The pressure was released and the reactor heated to 150° C. Sodium hydroxide solution (9.823% strength; 40.1 g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150° C. for a further 4 hours. The mixture was cooled, unreacted 2-chloro-6-trifluoromethylpyridine extracted with methylene chloride, and the aqueous phase acidified with hydrochloric acid and filtered to afford 2-hydroxy-6-trifluoromethylpyridine (5.615 g; 93% strength; 73% isolated yield). Further product was obtained by extraction of the filtrates with methylene chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:5][C:6]1[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl-].[Li+].C([C:27]1[C:32](O)=[C:31](C(C)(C)C)[CH:30]=[C:29](C)[CH:28]=1)(C)(C)C.N>O1CCOCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:4]([CH2:5][C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH3:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(Br)c1OC
Agent: N
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccccc2)c1OC
Yield: 46 %

Procedure:
138 mg of 5-(3-bromo-4,5-dimethoxy-benzyl)-pyrimidine-2,4-diamine, 98 mg of trimethyl-phenyl-stannate (Example 1a), 51 mg of lithium chloride, 25 mg of tetrakis-triphenylphosphinepalladium and a crystal of 2,6-di-t-butyl-p-cresol in 10 ml of dioxan are held at reflux under argon for 4 hrs. The yellowish reaction mixture is poured into about 10% aqueous ammonia and extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and chromatographed on silica gel with methylene chloride/methanol 9:1. 62 mg (46%) of 5-(5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a yellowish solid. Mass spectrum: peaks: inter alia at m/e: 336 (M+, 100%), 321 (28%), 305 (54%), 123 (36%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]I)=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][O:11]C=C)=[O:6].[CH3:30][NH2:31]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:31][CH3:30])=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCI)cc1F
Reactant: CN
Product: CNCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 32 %

Procedure:
The product of Example 15, Step E, 3,4-Difluoro-2-[2-fluoro-4-(3-iodopropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide was reacted with methylamine and then deprotected according to the general procedure of Example 15, Step F, to afford 3,4-difluoro-2-{2-fluoro-4-[3-(methylamino)propyl]anilino}-N-(2-hydroxyethoxy)benzamide as a pale brown solid (32%); m.p. (Et2O) 112-116° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.61 (v br s, 1 H), 7.57-7.50 (m, 1 H), 7.02-6.94 (m, 1 H), 6.93 (dd, J=12.4, 1.5 Hz, 1 H), 6.79 (dd, J=8.3, 1.5 Hz, 1 H), 6.65 (ddd, J=8.8, 8.8, 5.9 Hz, 1 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H), 2.66 (t, J=7.3 Hz, 2 H), 2.52 (t, J=7.6 Hz, 2 H), 2.41 (s, 3 H), 1.73 (q, J=7.5 Hz, 2 H). Not all exchangeable protons were observed. Anal. calcd. for C19H22F3N3O3.0.5H2O: C, 56.2; H, 5.7; N, 10.3. Found C, 56.2; H, 5.6; N, 10.2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[C:20](F)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CN1C(=O)CCC1.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[C:20]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CC(C)(C)N
Reactant: O=C(Nc1cnccc1Nc1cccc(F)c1F)c1cccnc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)Nc1ncccc1C(=O)Nc1cnccc1Nc1cccc(F)c1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
To a solution of N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-fluoropyridine-3-carboxamide (4.0 g, 11.6 mmol) in NMP (30 mL) was added t-butylamine (15.0 mL, 145.3 mmol) at RT. The reaction mixture was slowly heated to 100° C. and stirred at this temperature for 48 hr. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (4×100 mL), brine solution (100 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo gave N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-(tert-butylamino)pyridine-3-carboxamide (4.1 g, 89% yield), which was used as is in subsequent reactions; LC-MS: 398.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1C
Reactant: OB(O)c1cncnc1
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C
Yield: 5 %

Procedure:
The title compound was synthesized as described in Example 33 in 5% yield starting from 1-(2-Bromopyridin-4-yl)-4-fluoro-1-(4-methoxy-3,5-dimethylphenyl)-1H-isoindol-3-amine (400 mg, 0.91 mmol) and pyrimidin-5-ylboronic acid (124 mg, 1.00 mmol).