Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH3:30][S:31][C:32](=[N:35][C:36]#[N:37])SC.C(OCC)(=O)C>C(O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:32](=[N:35][C:36]#[N:37])[S:31][CH3:30])=[CH:27][CH:28]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: CSC(=NC#N)SC
Reactant: Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Yield: 54.1 %

Procedure:
To a solution of 4-[1-(R)-(3,4 bis(difluoromethoxy)phenyl)-2-(4-pyridinyl)ethyl]aniline (1.8 g, 4.4 mmol) in ethanol (20 ml) at room temperature was added dimethylcyanodithioimidocarbonate (1.3 g, 8.9 mmol). The mixture was heated at 70° for 72 h, cooled and the solvent removed in vacuo to give a yellow foam. The foam was subjected to flash chromatography (SiO2 ; eluant ethyl acetate) to give the title compound as a yellow foam (1.2 g). 1Hnmr (300 MHz, CDCl3) δ 2.46 (3H, s), 3.30 (2H, d, J 7.98 Hz), 4.23 (1H, t, J 7.84 Hz), 6.46 (1H, t, J 73.58 Hz), 6.48 (1H, t, J 73.51 Hz), 6.90 (2H, d, J 6.0 Hz), 7.02 (1H, d, J 8.38 Hz), 7.06 (1H, br), 7.16 (1H, d, J 3.0 Hz), 7.16 (1H, d, J 3.0 z), 7.18-7.25 (3H, c), 8.10 (1H, br) and 8.40 (2H, d, J 6.03 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9]OC1C=CC=CC=1NCC(=O)C1C=CC(Cl)=C(Br)C=1)([CH3:4])([CH3:3])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH:45]=[CH:46][C:47]=1[Cl:48])[C:34]([N:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44])[CH3:37])=[O:35]>>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[N:36]([C:34](=[O:35])[C:33]1[CH:45]=[CH:46][C:47]([Cl:48])=[C:31]([Br:30])[CH:32]=1)[CH3:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCOc1ccccc1NCC(=O)c1ccc(Cl)c(Br)c1
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC(=O)OC(C)(C)C

Procedure:
4-{2-[(3-Bromo-4-chloro-benzoyl)methyl-amino]-phenoxy}-butyric acid tert-butyl ester (6.24 g) was similarly prepared according to Step 3C as a light yellow solid from 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (7.9 g, 23.2 mmol). MS [M-tert-but]+: 426.0/428.0; tR=2.69 min. (method 1)
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].ClC1C=C(C=C([F:25])C=1)C(O)=O>>[CH:12]1([C:9]2[CH:8]=[C:3]([CH:2]=[C:11]([F:25])[CH:10]=2)[C:4]([OH:6])=[O:5])[CH2:14][CH2:13]1
Reactant: COC(=O)c1cc(C2CC2)ccc1N
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Product: O=C(O)c1cc(F)cc(C2CC2)c1
Yield: 16 %

Procedure:
Obtained (16% yield) following the procedure described in intermediate 8 (step A), starting from 3-chloro-5-fluorobenzoic acid.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[OH:29])=O>CCOC(C)=O>[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:15][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[OH:29])[N:14]=1
Reactant: COC(=O)CCCCC(N)=S
Reactant: COc1ccc(C(=O)CBr)c(O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Temperature: 25 °C
Yield: 165.9 %

Procedure:
Add THF (50 mL, anhydrous) to a roundbottom flask containing 5-thiocarbamoyl-pentanoic acid methyl ester-(2.63 g, 15.0 mmol) and 2-bromo-1-(2-hydroxy-4-methoxy-phenyl)-ethanone (4.90 g, 15.0 mmol, 75% pure). Heat to reflux under N2 overnight. Cool to room temperature, add EtOAc, wash with saturated NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 8 grams of a yellow solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes followed by flash chromatography on silica gel eluting with CHCl3 to afford the title compound (2.69 g, 56%). MS (IS) 322 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[N:15]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCC1CCCCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12

Procedure:
130 g of 3-(cyclohexylmethoxy)pyridine-2-amine (Example 7A; 630 mmol, 1 equivalent) were initially charged in 3950 ml of ethanol, and 436 ml of ethyl 2-chloroacetoacetate (3.2 mol, 5 equivalents) were added. The resulting reaction mixture was heated under reflux for 24 h and then concentrated under reduced pressure. The crude product obtained in this manner was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase, giving 66.2 g (33.2% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(O)(=[O:14])C.C(OO)(=O)C>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Yield: 83 %

Procedure:
23.4 gms (0.109 mole) of 2-acetamido-6-bromopyridine was dissolved in 200 ml. of glacial acetic acid containing 27.6 ml (0.218 mole) of 7.9M peracetic acid and the solution was heated at 70° C for 2 hours and at 55° C for 19 hours. The reaction mixture was diluted with 1600 ml water and the solution was then concentrated in vacuo to 550 ml. 8.6% of unreacted-2-acetamido-6-bromopyridine was removed by filtration. The solvent was evaporated from the filtrate giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which was purified by treatment with activated charcoal to remove the yellow impurity and subsequently recrystallized from 2-propanol. A second recrystallization from 2-propanol gave fine white needles, m.p.=180.0°-180.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[N:7][C:2]=1[NH:35][C:34]1[CH:36]=[CH:37][C:31]([CH:28]2[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]2)=[CH:32][CH:33]=1)#[N:23]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cnc3C#N)cc2)CC1
Temperature: 115 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 240 mg, 0.71 mmol), 4-(1-methylpiperidin-4-yl)aniline (280 mg, 1.42 mmol), fine-powder cesium carbonate (930 mg, 2.84 mmol), Pd(OAc)2 (32 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 15% MeOH in chloroform to isolate (R)-tert-butyl 1-(5-cyano-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (204) in >90% yield. It was dissolved in 30 mL MeOH and 3 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water, concentrated in vacuo to dryness to give crude (R)-tert-butyl 1-(5-carbamoyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (205). It was treated with 40 mL commercial 4N HCl in dioxane for 40 min, and concentrated in vacuo to afford crude (R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (206) hydrochloride. Crude 206 hydrochloride (60 mg, 0.12 mmol) was dissolved in 3 mL DMF. To it were added DIEA (210 μL, 1.2 mmol) and dimethylcarbamoyl chloride (34 μL, 0.36 mmol). The mixture was stirred at RT for 1.5 hour, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-O-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (207) as HCl salt (36 mg). MS found for C25H36N8O2 as (M+H)+ 481.2, (M−H)− 479.3. UV: λ=268, 277, 306, 336, 372 nm.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[NH:23][N:22]=2)[CH:14]=1>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:30]/[C:26]1[CH:25]=[C:24]2[C:29]([C:21]([C:20]#[C:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(C#Cc4cccnc4)n[nH]c3c1)C(=O)N2
Yield: 53.2 %

Procedure:
The title compound (34 mg, 53%) was synthesized as a orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-methoxylindolin-2-one (29 mg, 0.18 mmol) and 3-(pyridin-3-ylethynyl)-1H-indazole-6-carbaldehyde (40 mg, 0.163 mmol), followed by additional 90 min with additional 5-methoxylindolin-2-one (5.8 mg, 0.036 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, br, 1H, NH), 10.46 (s, 1H, NH), 8.90 (s, 1H), 8.63 (d, J=4.4 Hz, 1H), 8.12 (dt, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=4.8 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 6.86 (dd, J=8.0 Hz, J=2.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.59 (s, 3H); MS ESI 393.2 [M+H]+, calcd for [C24H16N4O2+H]+ 393.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)[O:4][CH2:3]1.[CH3:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH3:16][CH2:17][CH2:18][CH:19]([NH:1][CH:2]1[CH2:6][C:5]2([CH2:7][CH2:8][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH2:11]2)[O:4][CH2:3]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)CCC
Reactant: CC(C)(C)C1CCC2(CC1)CC(N)CO2
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCC(CCC)NC1COC2(CCC(C(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To 3-amino-8-t-butyl-1-oxaspiro(4,5)-decane (1.12 g, 5 mmol) and heptane-4-one (0.6 g, 5.25 mmol) in dry methanol (20 ml) was added zinc chloride (0.41 g, 3 mmol). The mixture was stirred at room temperature for 5 minutes and sodium cyanoborohydride 0.38 g, 6 mmol) was added and the resulting heterogeneous mixture was stirred at room temperature overnight. The solvent was then stripped off in vacuo, toluene (50 ml) and 2N NaOH (50 ml) was added. The aqueous phase was extracted twice with toluene (2×50 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The resulting oil was purified by flash chromatography to give a pale yellow oil (1.12 g). nD :1.4726.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:11]#[C-:12].[Na+].[Na+]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:11]#[CH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#[C-]
Reactant: ICCCC1CCCCC1
Agent: [Na+]
Product: C#CCCCC1CCCCC1

Procedure:
The title compound was synthesized using 3-cyclohexyl-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:25][CH:24]=2)=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cncc3ccccc23)cc1

Procedure:
Intermediate 10A was prepared from 4-bromoisoquinoline and 4-(tert-butoxy carbonylamino)phenylboronic acid by the procedure described for the preparation of Intermediate 1C, and was obtained as an off-white foam (63% yield). MS (ES): m/z=321.2 [M+H]+. HPLC Ret timea: 2.432 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (s, 9 H) 7.44 (d, J=8.53 Hz, 2 H) 7.65 (d, J=8.53 Hz, 2 H) 7.68-7.75 (m, 1 H) 7.75-7.82 (m, 1 H) 7.88 (d, J=8.53 Hz, 1 H) 8.20 (d, J=7.78 Hz, 1 H) 8.40 (s, 1 H) 9.31 (s, 1 H) 9.57 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2.Cl>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2)=[O:10]
Reactant: NCC12CCCN1CCC2
Reactant: COC(=O)CN1CCCC1=O
Agent: Cl
Product: O=C(CN1CCCC1=O)NCC12CCCN1CCC2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture consisting of 14.1 g (89.6 mmol) of methyl 2-oxo-1-pyrrolidineacetate and 11.4 g (81.4 mmol) of 7a-(aminomethyl)pyrrolizidine was heated and stirred for 6 hours at 80° C. under argon atmospher. After cooling, the reaction mixture was then solved with 1.0N-hydrochloric acid and extracted 3 times with dichloromethane. An aqueous layer was rendered alkaline by the addition of sodium hydroxide solution and extracted 3 times with dichloromethane followed by drying over anhydrous magnesium sulfate. After removal of the drying agent through filtration, the solvent was evaporated under reduced pressure to obtain a yellowish oil as a free base of the desired compound. The free base was converted to terephthalate by usual manner. Yield: 32.0 g (91.1%).
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C([Li])(C)(C)C.[CH:15]1([CH2:21][C:22](=[O:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([CH2:21][C:22]([CH2:9][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=2)([OH:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Cc1cc(C)nc(C)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of collidine (0.113 g) in THF (1 mL) cooled to −70° C. was added dropwise over 3 minutes tert-butyl lithium (1.7 M in pentane, 0.55 mL). The mixture was stirred for 5 minutes and then 1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 15) (0.095 g) in THF (0.5 mL) was added dropwise. After 10 minutes at −70° C., the reaction was quenched by addition of EtOH (0.2 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated. The residue was fractionated by preparative layer chromatography (developer: methylene chloride-EtOAc (99:1)) followed by preparative layer chromatography (developer:hexanes-methylene chloride-EtOH (1:1:0.01)) to give the title compound as an oil (73 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[H-].[Na+].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:3]1=[O:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCN(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 15.2 %

Procedure:
A solution of 0.30 g (2.6 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one from step A above in 5 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.16 g (4.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.62 g (3.2 mmol) of tert-butyl bromoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 0-5% methanol in ethyl acetate gradient to afford the title compound as a clear oil (0.090 g, 15%). 1HNMR (500 MHz, CDCl3) δ: 3.88 (s, 2H), 3.23 (t, J=6 Hz, 2H), 3.20 (t, J=6 Hz, 2H), 2.84 (s, 3H), 1.94-1.89 (m, 2H), 1.37 (s, 9H). LC-MS: m/z (ES) 229 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH3:33])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: Cc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-methylaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
N2-isobutyryl-2′-deoxyguanosine (20.5 g) was dissolved in 200 ml of DMF. After 18.5 g of imidazole was dissolved in the resultant solution by addition, 21.4 g of tert-butyldimethylsilyl chloride was then added. DMF (100 ml) was further added and the solution was stirred at room temperature. After 8 hours, extraction using chloroform was carried out and the organic layer was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After concentration of the extract, the target compound was separated by column chromatography (methanol/chloroform). The fraction solution including the target compound was prepared and concentrated to obtain 20.5 g of the titled compound (yield; 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]2[N:25]([C:28](=[O:44])[CH:29]([NH:36]C(OC(C)(C)C)=O)[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:27][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]2[N:25]([C:28](=[O:44])[CH:29]([NH2:36])[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:27][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 39 (460 mg, 0.76 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL). After 2 h, the solution was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 40 (366 mg) as a pale yellow-colored foam that was used without further purification. Mass spectrum, m/z [505.5] (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12].Cl>>[ClH:5].[CH2:1]([N:19]1[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[C@H:17]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC[C@@H]1CN1CCCC1
Agent: Cl
Product: C=CCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@H](CN2CCCC2)C1
Yield: 81 %

Procedure:
The compound was prepared by coupling of allyl bromide with 1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine in 81% yield; mp: (HCl salt)157-160° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-2.0 (6H m), 2.3-3.0 (6H, m), 3.1-3.8 (4H, m), 4.3-4.8 (1H, m), 4.9-5.1 (2H, m), 5.7-5.9 (1H, m), 7.0-7.3 (3H, m); MS (FAB) 396 (M+H)+; Anal. Calcd for C20H27Cl2N3O.2HCl: C, 51.19; H, 6.23; N, 8.95. Found: C, 50.89; H, 6.42; N, 8.65.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[CH3:32][NH:33][CH:34]1[CH2:36][CH2:35]1.Cl>CN(C=O)C>[F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:33]([CH:34]2[CH2:36][CH2:35]2)[CH3:32])[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CNC1CC1
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N(C)C1CC1
Yield: 14.6 %

Procedure:
To a mixture of 6.0 g (0.017 mol) of product from Example 105, 1.71 g (0.017 mol) of triethylamine in 30 ml of DMF was added 1.76 g (0.025 mol) of N-methylcyclopropylamine at such a rate that the temperature remained below 30° C. After 4 hours the reaction mixture was poured into 3.7% HCl and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 5.8 g of a green oil. The crude product was purified by HPLC in 5% ethyl acetate/cyclohexane, followed by kugelrohr distillation at 67 Pa, oven temperature 150° C., affording 1.02 g (15.5%) of product as a green oil, nD25 1.4758.