Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])=[O:7].Cl.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][N:24]([CH3:25])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=1
Reactant: O=C(Cl)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: CNC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The product from step (i) above was dissolved in dry toluene (10 ml). Dimethylamine hydrochloride (1.3 g) was added followed by triethylamine (1.94 g). The mixture was then stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate and washed successively with ethyl acetate and washed successively with 2N sodium carbonate, 2N hydrochloric acid then water. The organic phase was dried then evaporated to yield a red-brown gum which was triturated in hexane to yield the title product as a beige solid (0.64 g), m.p.100°-103° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2)[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cc2cc[nH]c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 9.9 mmol) in CH2Cl2 (30 mL) was added MnO2 (4 g, 46 mmol). The mixture was stirred at room temperature for 8 h. The solid was filtered off and the filtrate was concentrated to dryness to give crude 5-ethyl-6-nitro-1H-indole (1.9 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([F:14])([F:13])[F:12])[C:6]([N+:21]([O-])=O)=[CH:5][CH:4]=1.C(OCC)(=O)C>C(O)(=O)C.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([F:12])([F:13])[F:14])[C:6]([NH2:21])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(OC(c2cccnc2)C(F)(F)F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(N)c(OC(c2cccnc2)C(F)(F)F)n1
Reaction time: 1.7 h
Yield: 41 %

Procedure:
6-Methoxy-3-nitro-2-[2,2,2-trifluoro-1-(pyridin-3-yl)-ethoxy]pyridine (243 mg, 0.738 mmol) was dissolved in acetic acid (3.6 mL) and water (3.6 mL). To this, reduced iron (124 mg, 2.21 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred for 1.7 hours. After water and brine were added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with saturated sodium bicarbonate and brine, and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=30/1) to give Compound HA (89.6 mg, yield: 41%).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:19]([O:21][CH3:22])=[O:20])=[C:4]1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[C:30]1([C:36]2[CH:40]=[C:39]([CH:41]=O)[O:38][N:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:19]([O:21][CH3:22])=[O:20])=[C:4]1[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:41][C:39]2[O:38][N:37]=[C:36]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:40]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: COC(=O)c1c(CC2CCNCC2)c(=O)c2ccccc2n1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(CC2CCN(Cc3cc(-c4ccccc4)no3)CC2)c(=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of the compound prepared in Example 306 (83.0 mg) and the compound prepared in Example 7 (52.2 mg) in dichloromethane (5.0 mL) was added diisopropylethylamine (0.105 mL) and sodium triacetoxyborohydride (85.2 mg). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=9:1) to obtain the title compound (72.0 mg) having the following physical data.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[CH:4]=1.[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@@H:9]2[O:10][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:4]=1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cccnc1)N1CCCC1
Yield: 35.7 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.55 g, 9.80 mmol) in methanol (10 mL) were added a mixture of 3-pyridine carboxaldehyde (1.03 mL, 10.84 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.50 g, 10.86 mmol). The solution was stirred 3 h at 0° C. and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water. The organic layer was combined with two additional ethyl acetate extracts (2×100 mL), washed with aqueous sodium chloride and dried over MgSO4, filtered and evaporated. Concentration afforded a crude product which was purified by column chromatography on silica (CH2Cl2:MeOH=98:2) to yield to trans-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04110B (0.95 g, 39%) as a pale yellow pale solid.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:25]
Reactant: C=O
Reactant: CNC
Reactant: O=C(CCCCCc1ccccc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.403 g (1.355 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.15 g (1.6 mmol) of 50% aqueous dimethylamine and 0.13 g (1.6 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(Cl)Cl>[OH:25][CH2:24][CH2:26][NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCO
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (4 g, 0.037 mol.) and N-hydroxysuccinimide (6.3 g, 0.055 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (9.5 g, 0.055 mol) in 10 mL of DCM. The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature, the reaction mixture was filtered and the precipitate was washed with 2×10 mL of dichloromethane. The combined filtrate was evaporated and dissolved in 20 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of Ethanolamine 23 (3.3 mL, 2.5 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give ethyl (2-hydroxyethyl)carbamate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(N(CC)CC)C>O1CCOCC1.C(OCC)(=O)C>[C:6]([NH:8][C@H:9]([C:17]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)CN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 0.86 g (2 mmol) of pentafluorophenyl N-t-butyloxycarbonyl-L-phenylalaninate, prepared according to Example 48, in 10 ml of dioxane, 0.28 g (2.2 mmol) of ethyl glycinate (hydrochloride) and 0.31 g (3 mmol) of triethylamine are added simultaneously. The mixture is stirred for one hour at room temperature. It is diluted with 10 ml of ethyl acetate and washed with aqueous 0.1N hydrochloric acid, potassium bicarbonate and sodium chloride solutions. The organic phase is dried over magnesium sulphate and evaporation. The residue is taken up with a 4:6 ethyl acetate/hexane mixture and filtered on silica. After evaporation, 0.53 g (Y=76%) of BOC-Phe-Gly-OEt is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[Br:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH:9]([C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1c(Cl)cccc1I
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOCCBr)c1c(Cl)cccc1I
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of ethyl 2-(2-chloro-6-iodophenyl)acetate (4.5 g, 14 mmol) in 12 mL DMF was stirred at room temperature and treated with sodium hydride (0.80 g, 35 mmol). The mixture turned to orange and was stirred for 10 minutes. The mixture was treated dropwise with 1-bromo-2-(2-bromoethoxy)ethane (4.2 g, 18 mmol) in 12 mL DMF. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then warmed to 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and quenched carefully with 20 mL H2O, extracted with ether (3×100 mL). The combined organic layers were washed with water (3×50 mL), 20 mL saturated NaCl, dried over anhydrous Na2SO4, and concentrated to give 5.8 g of the crude product as a yellow oil. MS m/e: (M+H)+ 475/477.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]4[CH2:20][CH2:19]4)[C:15](=[O:21])[NH:14][C:13]=3[CH:22]=2)[C:5]([F:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[N:30][NH:31]2)=[CH:27][CH:26]=1>>[CH2:19]1[CH2:20][CH:18]1[CH:16]1[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[C:9]([NH:8][C:6]3[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:33]=[C:32]5[C:28]([CH:29]=[N:30][NH:31]5)=[CH:27][CH:26]=4)[N:7]=3)[CH:10]=[CH:11][C:12]=2[O:17]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2cc(Nc3nc(Cl)ncc3F)ccc2OC1C1CC1
Product: O=C1Nc2cc(Nc3nc(Nc4ccc5cn[nH]c5c4)ncc3F)ccc2OC1C1CC1

Procedure:
In like manner to the preparation of N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-4-pyrimidineamine and 6-aminoindazole were reacted to yield the desired product N4-[2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]oxazin-6-yl]-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.06 (m, 2H), 7.82 (s, 1H), 7.53 (d, 4H), 7.39 (dd, 1H), 7.22 (m, 2H), 6.83 (d, 1H), 1.19 (m, 4H); LCMS: retention time 9.29 min; purity 90%; MS (m/e): 418 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 40.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (132 mg, yield: 40.2%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([OH:25])=[O:24].[CH2:36]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([O:25][CH3:36])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccsc1C(=O)O[C@]1(C(=O)O)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2sccc2C)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (11.1 g) is dissolved in ethyl acetate (200 mL). DBU (4.05 g) and dimethyl sulphate (3.36 g) are added sequentially and the reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords 3-methylthiophene-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 0.90 (3H, d), 0.92 (3H, s), 1.40 (3H, s), 2.40 (3H, s), 3.65 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:36]([F:39])=[N:37][CH:38]=1.C([O-])(=O)C.[K+]>O>[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[CH:34]=[C:35]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)[C:36]([F:39])=[N:37][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CC1(C)OB(c2cc(C3OCCO3)cnc2F)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4OCCO4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51; (2.102 g, 5.462 mmol), 5-(1,3-dioxolan-2-yl)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Example 234; 1.901 g, 6.442 mmol), Am-Phos (200.6 mg, 0.2833 mmol), and potassium acetate (1.51 g, 15.4 mmol) were suspended in water (4 mL) and 1,4-dioxane (20 mL) and nitrogen was bubbled through the suspension for 30 s. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred under nitrogen for 4 h. Then, the reaction was cooled to room temperature, treated with water (40 mL), and extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered through a Celite® (diatomaceous earth) pad, and concentrated. The crude material was purified on a silica gel filter (600 mL fritted funnel with about 3 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH) to give 4-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.175 g). 1H NMR (CDCl3, 400 MHz) δ 8.65 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.42 (d, J=1.37 Hz, 1H), 7.23 (dd, J=8.41 Hz, 5.87 Hz, 4H), 6.87 (dd, J=10.27 Hz, 8.71 Hz, 4H), 5.93 (s, 1H), 4.83 (s, 2H), 4.81 (s, 2H), 4.17-4.04 (m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 2.55 (s, 3H). m/z (ESI, +ve ion) 518 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:45]#[C:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:10][C:11]=1[N:12]([C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[CH:13]1[CH2:18][CH2:17][C:16]([O:26][C:27]([CH:29]2[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])([CH2:19][O:20][CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH2:15][CH2:14]1)=[O:6].C1COCC1.O>CO>[CH3:49][C:47]([CH3:48])([CH3:50])[C:46]#[C:45][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([N:12]([C:36]([CH:38]2[CH2:39][CH2:40][CH:41]([CH3:44])[CH2:42][CH2:43]2)=[O:37])[CH:13]2[CH2:14][CH2:15][C:16]([O:26][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])([CH2:19][O:20][CH:21]3[CH2:25][CH2:24][O:23][CH2:22]3)[CH2:17][CH2:18]2)[CH:10]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(COC2CCOC2)(OC(=O)C2CCC(C)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(C(=O)OC2(COC3CCOC3)CCC(N(C(=O)C3CCC(C)CC3)c3cc(C#CC(C)(C)C)sc3C(=O)O)CC2)CC1
Temperature: 70 °C
Yield: 29.7 %

Procedure:
NaOH (1.17 mL of a 1.0N aqueous solution) was added dropwise to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-cyclohexanecarbonyloxy)-4-(tetrahydro-furan-3-yloxymethy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (80 mg, 0.117 mmol) in methanol (2 mL)/THF (2 mL)/H2O (2 mL) at room temperature. The solution was heated at 70° C. overnight and then cooled to room temperature. Volatiles were removed under vacuum and the resulting residue purified by HPLC with CH3CN (0.1% TFA)/H2O (0.1% TFA) to provide the Compound 4 (23.3 mg, 36%) as colorless solid. MS (m/z): 546.0[M+H]+; HPLC retention time 4.169 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16].CNC.[H][H]>[Ni].CO.O>[CH3:8][C:9]1[C:10]([OH:16])=[C:11]([CH2:3][C:2]([CH3:1])([CH3:7])[CH2:5][OH:6])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CC(C)(C=O)CO
Reactant: Cc1ccc(O)c(C)c1
Reactant: [H][H]
Agent: [Ni]
Agent: CNC
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(O)c(CC(C)(C)CO)c1
Reaction time: 20 h
Yield: 60 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 109 g (0.9 mol) of 2,4-dimethylphenol, 24 g (0.22 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave under autogenous pressure of 20-30 bar at 160° C. for 20 h and then at 180° C. for 20 h. After the autoclave has cooled and the pressure has been released, 95 g of Raney Ni (0.1 parts based on complete mixture) are added to the reaction mixture and hydrogenation is carried out at 140° C. under 80 bar of hydrogen for 20 h. After filtration and removal of volatiles by distillation, the residue is recrystallized from methanol/water 10:3. 112 g (60%) of 3-(3,5-dimethyl-2-hydroxyphenyl)-2,2-dimethylpropanol are obtained (melting point 117° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:25])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2cnn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10 mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed by iodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for 3 h, saturated aqueous ammonium chloride (30 mL) was added and the mixture extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%): MS (ES) m/z 340(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23]C[CH2:21][C@@H:20](NCCNC)[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:30]([N:33](C(C)C)[CH2:34]C)(C)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC([N+]([O-])=O)=CC=1.[CH3:61][N:62]([CH:64]=[O:65])[CH3:63]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:19][CH2:20][CH2:21][C@@H:61]([N:62]5[CH2:63][CH2:30][N:33]([CH3:34])[C:64]5=[O:65])[CH2:23]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CN(C)C=O
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Product: CN1CCN([C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flask containing (1S,3R)—N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine, 47c, (0.020 g, 0.048 mmol) in DMF was added diisopropylethylamine (0.025 mL, 0.144 mmol) and bis(4-nitrophenyl) carbonate (0.016 g, 0.053 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The resulting residue was purified by HPLC using 5-70% MeOH/H2O with 6 mM HCl to provide the desired product.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[PH2](O)=O>I.O>[CH3:7][C:8]1[NH:9][C:10]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CCC(=O)CC
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: I
Agent: O=[PH2]O
Solvent: O
Product: CCC(CC)c1[nH]c(C)c(C(C)=O)c1C
Reaction time: 4 h

Procedure:
3-Pentanone (0.85 ml) was added to a solution of 548 mg of 2,4-dimethyl-3-acetyl-pyrrole, in 10 ml of aq. hydriodic acid, 10 ml of acetic anydride and 2 ml of hypophosphorous acid. The solution was stirred for 13/4 hours then poured into 200 ml of water to precipitate the product as tiny nearly colourless prisms (651 mg, 79%), m.p. about 186°-189° C. For analysis it was recrystallized from ethanol as colourless plates, m.p. 188.5° C. after a solid phase change at 135°. Anal. Calc. for C13H21NO: C, 75.31; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.04; N, 6.78.