Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:11][C:10]=1[C:16]#[N:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1C#N
Reaction time: 1 h
Yield: 81.5 %

Procedure:
t-Butyl(4-amino-2-cyanophenoxy)acetate (430 mg) obtained in Reference Example 50(1) is dissolved in tetrahydrofuran (10 ml), is added saturated sodium hydrogen carbonate solution (10 ml), and then is added benzyl chloroformate (355 mg) under ice-cooling. Under ice-cooling, the reaction solution is stirred for 1 hour and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 followed by 3/1) to give t-butyl(4-benzyloxycarbonylamino-2-cyanophenoxy)acetate (540 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:11].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([N:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:6]2=[O:11])[S:29]([CH3:28])(=[O:31])=[O:30])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N)c2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(S(C)(=O)=O)S(C)(=O)=O)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of tert-butyl 2-(4-amino-1,3-dioxoisoindolin-2-yl)acetate (712 mg, 2.58 mmol), triethylamine (1029 μl, 7.73 mmol) and methanesulfonyl chloride (602 μl, 7.73 mmol) in 20 ml of DCM was stirred overnight at room temperature. The mixture was washed with 1N HCl, brine and finally dried over sodium sulfate and evaporated; the residue was purified by flash chromatography (Hexane/EtOAc 3/1 to 1/1) yielding tert-butyl 2-(4-(N-(methylsulfonyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate as an off-white foam (0.96 g, 2.220 mmol, 86% yield, MS/ESI+ 454.8 [MNa]+) and used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:29])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([Cl:27])[CH2:12]3)[CH2:9][C@H:8]1[CH3:28])(=[O:3])[CH3:2].BrN1C(=[O:36])CCC1=O.Cl(O)(=O)(=O)=O>O1CCOCC1>[C:1]([O:4][CH2:5][C:6](=[O:29])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]4([O:36][C@H:22]4[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([Cl:27])[CH2:12]3)[CH2:9][C@H:8]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reactant: O=C1CCC(=O)N1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of 12.0 g of 21-acetoxy-6α-chloro-16α-methyl-1,4,9(11)-pregnatriene-3,20-dione in 120 ml of dioxane is stirred at room temperature after adding 11.1 g of N-bromosuccinimide and 60 ml of 10% perchloric acid and, after 60 minutes, poured into ice water. The thus-precipitated product is filtered off, washed with water, dried in the air, and dissovled in 215 ml of ethanol. After adding 29 g of potassium acetate, the solution is heated for 8 hours to 60° C. under argon. Then the mixture is concentrated to a volume of 60 ml under vacuum, and stirred into ice water. The precipitated product is isolated and chromatographed on silica gel. With 8-9% acetone-hexane, after recrystallization from acetone-diisopropyl ether, 5.2 g of 21-acetoxy-6α-chloro-9,11β-epoxy-16α-methyl-9β-pregna-1,4-diene-3,20-dione is obtained, m.p. 189° C. [α]D25 =+57° (chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1

Procedure:
Dissolve 4-(3-cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.2 g, 5.77 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) and hydrogenate with 10% palladium on carbon (300 mg) at 33 psi for 16 h. Filter the catalyst over celite and back-wash with 1:1 ethanol/ethyl acetate (50 mL). Concentrate to give a dark solid and dissolve in 1:1 ethyl acetate/hexanes (50 mL) and pass through a silica gel plug. Back-wash the plug with 1:1 ethyl acetate/hexanes (100 mL) and concentrate the filtrate to an oil, which solidifies upon standing and found to be pure title compound (2.0 g, 90%); 1H NMR DMSO-d6) δ8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.16 (m, 1H), 2.08 (m, 2H), 1.62 (m, 6H); MS (ESI) m/z 384 (m+H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[N+:2]=[N-:3].NN.O>C(O)C>[N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccccc1N
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a suspension of the of 2-(2-azido-phenyl)-isoindole-1,3-dione (373 mg, 1.4 mmol) in ethanol (10 mL) was added hydrazine (140 μL, 4.24 mmol) followed by stirring for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue which was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes to 33% ethyl acetate/hexanes gradient elution) to give 48 mg (25%) of 2-azidophenylamine as a solid: 1H NMR (300 MHz, DMSO-d6) δ 6.98 (m, 1H), 6.86 (m, 1H), 6.66–6.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Cl)cc2s1

Procedure:
Three grams of 6-chloro-1,3-benzothiazol-2-amine was dissolved in about 50 mL DMF. Next, about 2.5 mL of EtNCO was added followed by about 3.2 mL of triethylamine. The solution was allowed to react at about 80° C. for about 8 hours. The reaction solvent was then removed in vacuo and the crude oil was taken up in ether. The solids were isolated by filtration and washed with ether. The product was then dried in vacuo. 1H NMR 1.09 (t, 3H, J=7.2 Hz), 3.19 (m, 2H), 6.74 (br s, 1H), 7.37 (d, 1H, J=8.58 Hz), 7.60 (d, 1H, J=8.59 Hz), 8.01 (s, 1H), 10.8 (br s, 1H). LCMS: R.T. 2.3 min, MH-254 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[C:27]1([C:33]2([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:19])[NH:39][S:36]([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)(=[O:37])=[O:38])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reactant: NS(=O)(=O)C1(c2ccccc2)CC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)NS(=O)(=O)C2(c3ccccc3)CC2)C1

Procedure:
Compound 757 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 1-phenyl-cyclopropanesulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 50% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0026 g, 3% yield). HRMS (M−H) calcd for C26H30N3Cl2O6S: 582.12324. found: 582.1215.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]#[C:21][CH3:22])([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25]>>[OH:25][NH:24][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]#[C:21][CH3:22])[CH2:15][C:16]#[C:17][CH3:18]
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex4-ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmnol), 0.21 g of the product was isolated. Yield 77%; white solid; mp 161-163° C.; MS:338.1(M+H)+; 1H NMR (300 MHz, DMSO-d6) o 1.67(s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm-1): 3336s, 3245r, 168 Is, 1589m, 1493m;
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl>[N+:1]1([O-:20])[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCc2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1CCCc2c1ccc[n+]2[O-]
Reaction time: 4 h
Yield: 83.7 %

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (7.12 g) was dissolved in dichloromethane (138 mL), added with 3-chloroperbenzoic acid (14.5 g) under ice cooling, and stirred for 4 hours at the same temperature. After adding a saturated aqueous solution of sodium hydrogen carbonate and diluting with chloroform, insoluble was removed by filtration through Celite. After adding 1 mol/L aqueous solution of sodium hydroxide, it was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residues were suspended in diethyl ether and collected by filtration to obtain the title compound (6.61 g) as a yellow powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[CH3:6].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Cl:3])=[CH:10][CH:9]=1)[CH3:6]
Reactant: CCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (10.4 g, 87.7 mmol) was added dropwise to a 0° C. solution of 4-ethoxybenzyl alcohol (11.0 g, 72.4 mmol) in dry CH2Cl2 (150 mL) with a catalytic amount of DMF (1 mL). Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the residue dissolved in minimal THF and then precipitated in cold H2O to yield a white precipitate. The solid was collected, taken up in CH2Cl2, dried and concentrated. The resulting oil was solidified by cooling with CO2/acetone. The compound as a white solid, which decomposes upon melting 11.3 g(92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][N:4]=1.[C-]#N.[Na+].[CH3:14][N:15](C=O)C>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:14]#[N:15])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CCl
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ncccc1CC#N

Procedure:
4 g of (2-methoxy-3-pyridyl)methyl chloride, 2.5 g of sodium cyanide and 10 ml of DMF were stirred under heating for 10 minutes. Water was added thereto, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The drying agent was removed, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1), to give 2.5 g of a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2].Br[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:35][CH2:36][OH:37])=[O:16])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: OCCBr
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCO)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 94.2 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (170 mg, 355 μmol; Example 5A) was initially charged in dry DMF (4 ml), 2-bromoethanol (177 mg, 1.42 mmol; 4 eq.) and triethylamine (72 mg, 709 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 10 h. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×20 ml) and saturated sodium chloride solution (20 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (175 mg, 94% of theory).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH2:19])[CH3:14]>>[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCN(CC)CCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-diethylpropane-1,3-diamine as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[N:4][C:3]=1[NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccccc1
Temperature: 50 °C
Yield: 80 %

Procedure:
Part A. A solution of 5-amino-4,6-dichloropyrimidine (10.0 g, 61.0 mmol) and triethylamine (12.8 mL, 91.5 mmol) in ethanol (100 mL) was treated with benzylamine (7.30 mL, 67.1 mmol), and heated to 50° C. overnight. The resulting mixture was cooled, and the resulting crystalline solid was collected by filtration. The solid was triturated with hexane, refiltered and dried under vacuum. A second crop was collected from the mother liquor and purified like the first crop to afford in total 12.67 g (48.8 mmol, 80%) of 5-amino-6-benzylamino-4-chloropyrimidine. TLC RF 0.10 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.62 (1H, s), 7.13-6.97 (5H, m), 6.61 (1H, br t, J=5 Hz), 4.43 (2H, d, J=5.5 Hz), 4.24 (2H, br s). MS (NH3-CI): m/e 238 (4), 237 (33), 236 (15), 235 (100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[CH3:22][N:23]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:15][O:14][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH:23][CH3:22])=[N:32][CH:33]=3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:10]=1)([CH3:13])[CH3:12]
Reactant: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)c3nc(C(C)(C)OC)sc3n2)cn1

Procedure:
Crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (60 mg) was reacted with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate via general procedure A. This crude product was then treated with TFA to remove residual protecting group and purified via reverse phase HPLC to get 58.4 mg 102. MS (Q1) 401.2 (M)+.
Reaction SMILES: C([N:3]1[C@H:11]2[C@@:6]([CH3:20])([C:7]([CH3:19])([CH3:18])[C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:9]=3[CH2:10]2)[CH2:5][CH2:4]1)=O.Cl>C(O)CC.O>[CH3:17][O:16][C:12]1[C:9]2[CH2:10][C@@H:11]3[C@:6]([CH3:20])([CH2:5][CH2:4][NH:3]3)[C:7]([CH3:19])([CH3:18])[C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc2c1C[C@H]1N(C=O)CC[C@]1(C)C2(C)C
Agent: Cl
Solvent: CCCO
Solvent: O
Product: COc1cccc2c1C[C@H]1NCC[C@]1(C)C2(C)C
Yield: 100.1 %

Procedure:
9.6 g (35 mmol) of trans-1-formyl-8-methoxy-3a,4,4-trimethyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (5) are dissolved in 75 mL of n-propanol and mixed with 25 mL of conc. hydrochloric acid and 15 mL of water. The mixture is refluxed for 12 h, the alcohol is eliminated in vacuo and diluted with 800 mL of water. The mixture is extracted once with 150 mL of ethyl acetate (discarded), the aqueous phase is made alkaline with sodium hydroxide and extracted three times with 200 mL ethyl acetate. The combined organic phases are dried over MgSO4 and the solvent is eliminated in vacuo. 8.6 g (100%) of trans-8-methoxy-3a,4,4-trimethyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (6) are obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:13][CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9](=[O:12])OC)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([Mg]Br)[CH:24]=[CH2:25]>C1COCC1>[CH2:25]([C:15]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:9](=[O:12])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH:24]=[CH2:23]
Reactant: COC(=O)N(CCC(=O)c1ccccc1)c1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (250 mg, 0.69 mmol) in dry THF (2 mL) was added dropwise 1 M allylmagnesium bromide (10 mL) −78° C. The reaction mixture was stirred at rt for 3 h. The resulting mixture was quenched with sattd aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (120 mg, 47%). 1H NMR (400 MHz, CDCl3): δ=2.48 (m, 2H), 2.55-2.7 (m, 2H), 3.23 (m, 1H), 3.51 (m, 1H), 5.04 (m, 2H), 5.72 (m, 1H), 7.01 (m, 1H), 7.11 (m, 1H), 7.23 (m, 1H), 7.3 (m, 1H), 7.35 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].I[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCI
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1CCCNC(=O)OC(C)(C)C
Yield: 26.8 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 5.00 g (28.5 mmol) of methyl 2-indolecarboxylate, 1.26 g (31.4 mmol) of 60% sodium hydroxide, 12.3 g (43.2 mmol) of tert-butyl N-(3-iodopropyl)carbamate (prepared from 3-iodopropyl-amine and di-tert-butyl dicarbonate) and 60 ml of dimethylformamide. Thus, 2.54 g (27%) of methyl 1-(3-tert-butoxycarbonylaminopropyl)-2-indolecarboxylate was obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](Cl)=[O:12])=[CH:7][CH:6]=1>C(N(CC)CC)C>[I:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([N:2]([CH3:3])[CH3:1])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(Cl)COc1ccc(I)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COc1ccc(I)cc1
Reaction time: 2 h

Procedure:
Dimethylamine (33% w/w in IMS, 5.85 ml) was added dropwise to a suspension of (4-iodophenoxy)acetyl chloride (9.49 g) in triethylamine (50 ml) at 0° under nitrogen. The suspension was stirred for 2 h at 0° and partitioned between ethyl acetate (300 ml) and 8% aqueous sodium bicarbonate (300 ml). The organic layer was dried and the solvent was evaporated to leave an oil which was purified by FCC eluting with diethyl ether to give the title compound as a white solid (3.96 g), m.p. 63°-65°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.73 (m, 11 H), 1.88-2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J=13.8 Hz, 2 H) 4.81 (d, J=8.1 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J=13.4 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.ClC1C=C(OC)C=C(F)C=1C[N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(Cl)c1
Reactant: OCc1c(F)cncc1F
Product: COc1ccc(N2C(=O)N(Cc3c(F)cncc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (47 mg, 0.10 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol) and 3,5-difluoropyridine-4-methanol (109 mg, 0.75 mmol) using the methods of (113).