Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)=[O:7])([O-])=O.O.O.[Sn](Cl)Cl>CCO>[NH2:1][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:13][CH:14]=1)=[O:7]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4N)cc3)sc2c1
Yield: 13.7 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-nitro-N-[4-(6-methylbenzothiazol-2-yl)-phenyl]-benzamide (0.5 g, 1.28 mmol) and tin (II) chloride dihydrate (1.45 g, 6.42 mmol) in EtOH (50 ml) to give the title compound (0.063 g, 14%) as a tan needles after recrystallisation from EtOH.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2](=[O:1])[C:3]3=[CH:23][S:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]3=[N:5]2)=[CH:15][CH:14]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (55 mg, 0.17 mmol) was suspended in anhydrous dimethyl acetamide (1 ml). Diisopropyl-ethyl amine (46.5 mg, 0.36 mmol, 62 μl) was added followed by 3-dimethylaminopropylamine (17.5 mg, 0.17 mmol) and [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h and was purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 407 [M+H]+ Activity **
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:14](=[O:29])[C:15]1[C:20](SC)=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=1OC)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32](OC(=O)NC1CCCC1N)(C)C.C(C1C=C(C(F)(F)F)C=CC=1C(O)=O)C>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14](=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:20]=1[CH2:31][CH3:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Agent: CCc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C

Procedure:
The title compound, light yellow solid, MS: m/e=401.4 [(M+H)+], was prepared in accordance with the general method of intermediate N from [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[NH2:17].Cl[C:19]1[C:20]2[N:28]=[C:27](Cl)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([S:1][C:14]2[CH:15]=[C:16]3[N:8]=[C:9]([NH:17][C:19]4[C:20]5[N:28]=[CH:27][CH:26]=[CH:25][C:21]=5[N:22]=[CH:23][N:24]=4)[S:10][C:11]3=[N:12][CH:13]=2)=[N:3]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Nc1nc2cccnc2s1
Reactant: Cn1ccc(S)n1
Product: Cn1ccc(Sc2cnc3sc(Nc4ncnc5cccnc45)nc3c2)n1

Procedure:
The compound of Example 39 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-1-methylpyrazole, thiazolo[5,4-b]pyridin-2-yl-amine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[Br:24]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:24][C:13]1[NH:14][C:15]2[C:11]([N:12]=1)=[C:10]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@H:18]1[CH3:23])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@H:2]1[CH3:1])[N:16]=2
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)[nH]c2n1
Yield: 53.1 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purine (637 mg, 2 mmol) was dissolved in 50 mL of CH2Cl2 and stirred under argon. Bromine (124 μl, 2.4 mmol) was dissolved in 2 mL of CH2Cl2 and added within 2 minutes. The reaction was stirred for 6 hours at room temperature. 5 mL of aqueous Na2S2O3 were added, the mixture was stirred for 15 minutes, and the organic solvents were separated, washed with brine and aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 2/3 to 4/1) to give a foam (422 mg, 53%).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([N:30](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>ClC.O>[CH3:28][NH:30][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CCl
Agent: CN
Solvent: O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162 g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride (0.10 g, 0.86 mmol) and stirring was continued for 30 min at 0° C. To the above reaction mixture, methyl amine (40% solution) (0.124 mL) was added at 25° C. and stirring was continued for 1 h at 25° C. Water (20 mL) was added and extracted with ethyl acetate (2×20 mL). The combined organic extract was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (1:1) to afford the title compound as a colorless solid. mp : 80-82° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:14]([N:12]1[CH:13]=[CH:9][C:10]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)=[N:11]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ncccc1-c1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis (triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][NH:53][CH2:54][CH:55]([OH:60])[C:56]([F:59])([F:58])[F:57])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:62]=[CH:61][C:51]([CH2:52][N:53]([CH2:54][CH:55]([OH:60])[C:56]([F:59])([F:57])[F:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)C(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 30 mg (0.19 mmol) of 1H-indole-7-carboxylic acid and 60 mg of TBTU (0.19 mmol) in 6 ml DMF, were added 0.16 ml (0.93 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 85 mg (0.19 mmol) of [rac]-(4-tert-butyl-benzyl)-(3,3,3-trifluoro-2-hydroxy-propyl)-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (9 g silica gel; EtOAc/heptane 1:4) to give 17 mg white solid (17%). MS (EI) 418.2 (M)+.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:25]>CO.C(O)(C)C.C(OCC)C>[ClH:25].[ClH:25].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 4 g (11 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate (prepared as described in example 2.4) in 40 ml of methanol and 20 ml of a solution of hydrochloric acid in isopropanol, having a concentration of 5 or 6M, is stirred at 40° C. for 18 h and then concentrated under vacuum. The residue obtained is taken up in 200 ml of diethyl ether, filtered, and then dried under vacuum, 3.5 g (94%) of methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate dihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]O)[CH2:6][CH2:7][CH3:8].[CH2:19]([N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:19]([N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22].[B:1]([O-:4])([O-:3])[O:2][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCOCCOCCOCCO
Reactant: OB(O)O
Agent: CCCCN(CCO)CCCC
Solvent: Cc1ccccc1
Product: CCCCOCCOCCOCCOB([O-])[O-]
Reaction time: 8 h
Yield: 128.2 %

Procedure:
N,N-dibutylethanolamine/triethylene glycol monobutyl ether borate was prepared as follows. Boric acid (10.3 grams), triethylene glycol monobutyl ether (Fluka, 64.1 grams), and N,N-dibutylethanolamine (28.9 grams) were added to a 250 milliliter flask. One hundred fifty milliliters of toluene was then added. The reaction was allowed to proceed overnight at 110° C., and the byproduct water (˜9 grams) was continuously removed from the reaction by azeotropic distillation. The final solution was evaporated to remove toluene under vacuum, and a brownish liquid product (˜90 grams) of N,N-dibutylethanolamine/triethylene glycol monobutyl ether borate was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2cccs2)ccc1C(=O)O
Product: Cc1nc(-c2cccs2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (7 mg, 0.05 mmol) and 2-methyl-6-(2-thienyl)-nicotinic acid (10 mg, 0.05 mmol) as a yellow solid. 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.82 (dd, 1H), 8.58 (s, 1H), 8.34 (dd, 1H), 7.85-8.0 (m, 3H), 7.76 (m, 2H), 7.55 (dd, 1H), 7.48 (dd, 1H), 7.16 (dd, 1H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:12]2([CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:13]2)=[CH:20][CH:21]=1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a solution of p-cyanobenzaldehyde (1.6 g, 11.8 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (75 mL), was added 1N aqueous sodium hydroxide (1.0 mL, 1 mM). After the reaction solution was stirred at room temperature for two days, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give an orange liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a yellow crystalline solid (1.2 g, 38% yield), m.p. 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:32])([F:31])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([N:23]3[CH2:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][CH2:24]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][O:29][CH:26]2[CH2:27][CH2:28][N:23]([C:20]3([C:17]4[CH:18]=[CH:19][C:14]([O:13][C:12]([F:11])([F:31])[F:32])=[CH:15][CH:16]=4)[CH2:21][CH2:22]3)[CH2:24][CH2:25]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Solvent: C1CCOC1
Product: O=C(NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
4-Fluorophenyl isocyanate (0.062 ml, 0.546 mmol) was added to a solution of O-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yl)hydroxylamine (157 mg, 0.496 mmol) in tetrahydrofuran (5 ml) and the whole was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) to give 1-(4-fluorophenyl)-3-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yloxy)urea (221 mg, 98%) as a white solid: LCMS: 454 [M+1]+. 1H NMR (DMSO-d6) δ: 0.76 (s, 2H), 0.88 (s, 2H), 1.59 (m, 2H), 1.84 (m, 2H), 2.08 (m, 2H), 2.81 (m, 2H), 3.48 (m, 1H), 5.47 (s, 1H), 7.08 (m, 2H), 7.30 (m, 2H), 7.38 (m, 2H), 7.51 (m, 2H), 8.49 (s, 1H), 9.30 (s, 1H).
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.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]1.C(O)(C(F)(F)F)=O>>[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:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]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: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)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 (R)-tert-butyl 3-aminopiperidine-1-carboxylate as described in the General procedure for amide bond synthesis. The Boc group was then deprotected using TFA. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (m, 3H) 1.61 (m, 9H) 1.99 (s, 3H) 2.73 (m, 1H) 2.93 (m, 1H) 3.92 (s, 4H) 4.01-4.20 (t, J=14 Hz, 2H) 4.82 (m, 1H) 7.24 (d, J=6.8 Hz, 1H) 7.71-7.90 (m, 1H) 8.05 (s, 1H) 8.14-8.38 (m, 2H). [M+H] calc'd for C26H32F3N7O3, 548. found 548.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)[CH2:15][CH2:16]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 100 °C
Reaction time: 25.5 h
Yield: 23.4 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyrimidine (0.58 g, 3.60 mmol) and tert-butyl 3-amino-9-azaspiro[5.5]undecane-9-carboxylate (1.44 g, 5.37 mmol) in EtOH (25 mL) was added Et3N (0.86 g, 8.50 mmol). After addition, the reaction mixture was stirred at 100° C. in a sealed tube for 25.5 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a yellow solid (332.2 mg, 24%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].C(N(CC)CC)C.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>ClCCl>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:44])=[O:43])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.5 g; 1.27 mmole) was dissolved in dichloromethane (10 ml) and triethylamine (0.39 ml; 2.8 mmole) was added. The mixture was cooled to 0° C., Phenylmethanesulphonyl chloride (0.32 g; 1.68 mmole) was added. The reaction mixture was then stirred overnight and the temperature was allowed to reach room temperature. Water was added and the phases were separated. The organic phase was washed with water, dried with magnesium sulfate and evaporated. Chromatography of the residue on silica gel using ethyl acetate/heptane as eluant gave 0.245 g (38% yield) of 3-[4-{2-(4-benzylsulfonylaminophenyl)ethoxy}phenyl]-2-(S)-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:36]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-:36])=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: COCCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 3 h

Procedure:
A modification of the general method described in Part B of Example 3 was followed using 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-1H-imidazo[4,5-c]quinoline (5.4 g, 14 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. Dichloromethane (100 mL) was used as the solvent, and after three hours an analysis by TLC indicated the reaction was incomplete. Additional mCPBA (0.5 equivalents) was added, and the reaction was terminated after one additional hour. After the work-up the product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol to provide 1.5 g of 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:42]([F:43])=[CH:41][N:40]([CH3:44])[C:39](=[O:45])[CH:38]=1>>[F:43][C:42]1[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39](=[O:45])[N:40]([CH3:44])[CH:41]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1cc(F)c(Br)cc1=O
Product: C[C@@H](c1ccc(-c2cc(=O)n(C)cc2F)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-5-fluoro-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 76. Mass spectrum (ESI+): m/z=479 [M+H]+. The compound that had been obtained as an oil crystallized on standing. The solid was dried at 80° C. under vacuum. Melting points: 120-125° C. with evolution of gas followed by recrystallization and melting at 183-184° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:3].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]([C:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH:11][O:12][CH2:13][CH3:14])=[O:3]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC=C(C(C)=O)c1ccncc1

Procedure:
The process according to claim 2 where 4-pyridinylmethyl methyl ketone is first reacted with triethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone, said latter ketone is reacted with cyanoacetamide in the presence of at least a molar equivalent quantity of sodium hydroxide per mole of cyanoacetamide in methanol and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.