Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH:6]=1.O.O.[Sn](Cl)Cl>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Cl)c2)nc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(-n2cnc(Cl)c2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A vial was charged with 2-(4-chloro-1H-imidazol-1-yl)-5-nitropyridine (675 mg, 3.01 mmol), tin(II) chloride dihydrate (2.03 g, 9.02 mmol), and methanol (10 mL). The vial was sealed and heated to 90° C. and stirred for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20 mL) and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 6-(4-chloro-1H-imidazol-1-yl)pyridin-3-amine (380 mg, 65%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 8.20 (d, J=1.6 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.21 (dd, J=8.8, 2.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.O=S(Cl)Cl.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>[OH-].[Na+].C1COCC1>[ClH:13].[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([CH3:1])=[C:3]([C:14]([NH:24][C:23]([NH2:25])=[NH:22])=[O:16])[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC(=N)N)cnn1-c1cccc(Cl)c1
Yield: 12.7 %

Procedure:
A mixture of 5-methyl-1-(3-chlorophenyl)pyrazole-4-carboxylic acid (234 mg, 1.0 mmol) and 5 ml SOCl2 was heated to reflux for 45 min. Excess SOCl2 was removed in vacuo via codistillation with toluene. The residue was dissolved in 2mL of anhydrous THF and added dropwise over 30 minutes to a vigorously stirred 40° C. solution of guanidine hydrochloride (344 mg, 3.6 mol) in 3.25 mL 2 N NaOH and 1.9 mL THF. The resulting mixture was heated to reflux for 4 hours and then cooled. The organic solvent was removed in vacuo. The residue was diluted with 10 mL 1 N NaOH and extracted with 5×5 mL EtOAc. The combined organic layers were dried (Na2SO4) filtered and concentrated in vacuo to a white solid. This material was dissolved in 1 mL MeOH and 18.4 μL 12 N HCl was added with stirring. The solvents were removed in vacuo with toluene azeotropes and the resulting solid was stirred in 1 mL ether/acetone (1:1) and filtered to remove residual H2O. Drying under high vacuum at 40° C. afforded the desired product (20 mg, 6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:8]=2)=[CH:12][N:13]=[C:14]1[C:17]([OH:20])([CH3:19])[CH3:18]
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(C(C)(C)O)n5C)sc34)ccc2[nH]1
Yield: 64.1 %

Procedure:
2-[5-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol (190 mg, 0.62 mmol) and 2-methyl-5-aminoindole (108 mg, 0.714 mmol) were dissolved in 3 mL of t-butyl alcohol and 3 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 45 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (66%) of 2-{1-methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.40 (d, 1H), 7.02 (d, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 3.33 (s, 3H), 2.44 (s, 3H), 1.64 (s, 6H). LC-MS: 418, 419 (MH+); HPLC RT: 3.98 min.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>C(#N)C>[CH:26]1([NH:25][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: NC1CCc2ccccc21
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNC2CCc3ccccc32)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy]phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1-aminoindan and acetonitrile essentially as described above in example 35. Purity by LC/MS (APCI)=99%, [M+H]+=377.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[C:4]1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].N1C=CC=CC=1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>ClCCl>[CH:30]1([S:33]([N:21]2[CH2:20][CH2:19][N:18]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([C:5]=3[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=4)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(N2CCN(S(=O)(=O)C3CC3)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) is added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture is stirred at room temperature overnight. This is then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][C:18]([OH:20])([CH3:21])[CH2:17][NH:16][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)CN
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Solvent: c1ccncc1
Product: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Yield: 24 %

Procedure:
A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (300 mg, 1.4 mmol) and 1-amino-2-methylpropan-2-ol (137 mg, 147 μl, 1.54 mmol, 1.1 equiv.) in 3 ml of pyridine was heated 20 hours at 120° C. in a sealed tube. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane to ethyl acetate gradient to yield 90 mg (24% yield) of the title compound as a crystalline light yellow solid, MS: m/e=268.2 (M+H+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH2:24]([O:26][C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([CH2:33][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:35][CH:36]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCOC(=O)c1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 71.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (32.3 mg) and 4-ethoxycarbonylbenzyl bromide (28.1 mg) were used to obtain (2S,4S)-1-[[N-[4-(4-ethoxycarbonylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (34.7 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:14][CH2:13]1>C(#N)C>[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: N#CCCNc1ccccc1
Reactant: O=C(Cl)Oc1cccc(NC(=O)C2CC2)c1
Solvent: CC#N
Product: N#CCCN(C(=O)Oc1cccc(NC(=O)C2CC2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
29.2 g N-(2-cyanoethyl)-aniline is dissolved in 200 ml acetonitrile and then reacted with 23.97 g chloroformic acid-[3-(cyclopropylcarbonylamino)-phenyl]-ester with stirring, with which the temperature of the solution rises to about 35° C. After standing overnight the solvent is removed under vacuum, The remaining oily residue is treated with water, the water is decanted and the oil brought to crystallization with a 1:1 mixture of isopropyl ether/isopropanol. The crystallizate is finally recrystallized from isopropanol.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O)=[N+]=[N-].C(Cl)[Cl:22]>S(Cl)(Cl)=O>[Cl:22][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:1]=[C:4]2[C:5]=1[CH:16]=[CH:17][C:18]([F:20])=[CH:19]2
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Temperature: 0 °C
Yield: 95 %

Procedure:
2-Azido-N-(4-chloro-phenyl)-4-fluoro-benzamide (2.7 g, 1 mmol) was dissolved at ambient temperature in thionyl chloride (18.2 ml) under an argon atmosphere. The reaction mixture was heated under reflux conditions for 14 h and brought to dryness under reduced pressure. The residue was taken up in ice water/saturated aqueous NaHCO3 solution 1/1 and CH2Cl2. The layers were separated and the aqueous layer was extracted one more time with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (2.47 g, 8.8 mmol; 95%) as yellow solid. MS: m/e=280.9 [M+H+].
Reaction SMILES: [F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[CH:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])[CH2:4][C:3]1=O.[ClH:23].Cl.[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][NH2:31])[CH2:26]1>N1C=CC=CC=1>[ClH:23].[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30]/[N:31]=[C:3]2\[CH2:4][CH:5]3[C@:18]([CH3:20])([CH2:19][C@H:2]\2[F:1])[C@@H:17]2[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6]3)[CH2:26]1
Reactant: C[C@]12C[C@@H](F)C(=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C[C@@H](F)/C(=N/O[C@@H]3CCNC3)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
2α-Fluoroandrostane-3,17-dione (315 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 190 mg) were dissolved in pyridine (5 ml) and stirred at RT for 1 h. After evaporation of the solvent, the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the resulting oil obtained after fractions evaporation, dissolved in a 1/1 mixture of EtOAc/Et2O (20 ml) and cooled with an ice bath, an excess of 2N HCl solution in Et2O was added. The title compound I-bh was obtained, after filtration, as a white solid in 91% yield.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])=[C:4]([CH3:27])[CH:3]=1.Cl.O>C(O)C>[OH:17][CH2:16][CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]1[CH:20]=[C:21]([F:26])[C:22]([F:25])=[C:23]([F:24])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:27]
Reactant: C=COCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCO)cc(F)c(F)c1F
Yield: 74.7 %

Procedure:
A solution of 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-N-(2-vinyloxyethoxy)-benzamide (3.00 g, 6.09 mmol) in ethanol (80 mL) was treated with 1 M aqueous hydrochloric acid (16 mL, 16 mol). The resultant solution was stirred for 2.5 h at ambient temperature. Water (50 mL) was added and the slurry was filtered. The solids were washed with ethanol-water (1:1, 150 mL) and recrystallized from methanol-acetone to afford N-(2-hydroxyethoxy)-2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-benzamide (2.12 g, 75%): m.p. 205-207° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H), 8.13 (s, 1H), 7.54 (dd, J=8.9, 8.7 Hz, 1H), 7.47 (d, J=1.0 Hz, 1H), 7.32 9d, J=8.5 Hz, 1H), 6.41 (dd, J=8.1, 5.0 Hz, 1H), 4.69 (br s, 1H), 3.79 (br s, 2H), 3.52 (br s, 2H), 2.20 (s, 3H); MS (APCI+)=467.1; MS (APCI−)=465.1; Anal. Calcd/found for C16H14F3IN2O3: C, 41.22/41.28; H, 3.03/2.91; N, 6.01/5.79.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9](I)[O:8][C:7]=12.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.O>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:9]2[O:8][C:7]3=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1nccc2cc(I)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(-c2cc3ccnc(Cl)c3o2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
In a three-neck flask was placed a mixture of 7-chloro-2-iodofuro[2,3-c]pyridine (1.00 g, 3.58 mmol), 3,5-bis(trifluoromethyl)phenyl boronic acid (0.92 g, 3.6 mmol), 1,4-dioxane/water (50 mL/10 mL) and K2CO3 (0.74 g, 5.38 mmol). After the suspension was degassed with nitrogen for 15 min, (PPh3)2PdCl2 (0.12 g, 0.17 mmol) was added and the mixture was degassed with nitrogen for 5 min. The resultant mixture was stirred at 50° C. for 48 h under nitrogen. The mixture was then cooled to RT and the solvent was evaporated to give a black residue, which was purified by flash chromatography (2% MeOH:DCM) to afford 965 mg (74%) of the title compound as a white crystalline. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 7.50 (m, 4H), 7.94 (dd, J=1.5 Hz, 2.4 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CC[C@@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 881 heating at 140° C. Product was isolated as an off-white solid (43 mg, 39%). LCMS (m/e) 539 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.41 (broad s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (s, 2H), 5.81 (s, 1H), 5.62 (s, 1H), 4.27 (t, 1H, J=8.1 Hz), 3.97 (s, 4H), 3.72 (s, 3H), 3.39-3.54 (m, 2H), 3.08 (m, 4H), 2.88 (m, 2H), 2.75 (dd, 1H, J=11.9, 14.2 Hz), 2.49 (d, 1H, J=8.1 Hz), 2.42 (m, 3H), 2.20 (d, 1H, J=9.4 Hz), 1.61 (d, 1H, J=8.3 Hz), 1.50 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]3[CH:26]=[N:27][CH:28]=[CH:29][C:17]=3[NH:16][C:15]2=[O:30])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]3[CH:26]=[N:27][CH:28]=[CH:29][C:17]=3[NH:16][C:15]2=[O:30])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCNCC1

Procedure:
To a solution of 4.13.g (10.4 mmol) of 3-(1-benzylpiperidin-4-yl)-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine in 250 mL of methanol were added 1.89 g (30 mmol) of ammonium formate and 0.3 g of 10% palladium-carbon, and the mixture was heated under reflux for 5 hours. After being cooled, the reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer separated was dried on potassium carbonate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 10:100:900 aqueous ammonia methanol:chloroform) to give 2.67 g (8.66 mmol) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[CH2:10]2)(=[O:3])[CH3:2].C1N=C[N:35](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH2:35])=[O:19])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 73.9 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide was prepared by the procedure of example 6 from 3-[7-(acetylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.6 g, 1.3 mmol), CDI (0.3 g, 2 mmol) and NH4OH (0.20 ml, 2.6 mmol) in THF (30 ml) to give 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide as white solid (0.43 g, 72%): mp 129-131° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.97 (dd, J=5, 15 Hz, 1H, CH2), 3.42 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.40 (broad, 1H, NH2), 5.56 (m, 1H, CHN), 6.01 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.95 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.47 (d, J=7.5 Hz, 1H, Ar), 10.25 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 3.2, 14.4, 16.2, 24.4, 37.7, 46.7, 51.7, 64.2, 93.9, 113.0, 116.6, 117.2, 117.5, 119.2, 121.3, 132.8, 137.0, 138.2, 139.0, 142.2, 149.8, 168.0, 168.5, 171.0; Anal. Calcd. for C22H23F2N3O5: C, 59.06; H, 5.18; N, 9.39. Found: C, 58.48; H, 5.12; N, 9.65.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (75 mg, 0.21 mmol), tert-butyl [(3R,4S,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (62 mg, 0.16 mmol) and HATU (196 mg, 0.515 mmol) in DMF (2.0 mL), DIPEA (123 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25 mg, 29%). LCMS calc. for C24H27F2N6O3S (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.78 (s, 1H), 7.64-7.46 (m, 3H), 7.24 (t, J=8.6 Hz, 2H), 4.47 (t, J=9.1 Hz, 2H), 3.97 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.87-2.79 (m, 2H), 2.79-2.72 (m, 1H), 2.63 (dd, J=10.8, 4.6 Hz, 1H), 2.60-2.55 (m, 1H), 1.85-1.76 (m, 1H), 1.39 (br, 2H), 0.98 (s, 3H), 0.73 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:17]=[C:16]([NH:18][C@H:19]([C:29](O)=[O:30])[CH2:20]C3C=CC(OC)=CC=3)[O:15][C:14](=[O:32])[C:13]=2[C:33]=1[CH3:34])=[O:6])[CH3:3].[N:36]1(C(N)=O)[CH2:41]COC[CH2:37]1>>[CH3:37][N:36]([CH3:41])[C:29](=[O:30])[C@H:19]([CH3:20])[NH:18][C:16]1[O:15][C:14](=[O:32])[C:13]2[C:33]([CH3:34])=[C:9]([CH2:8][NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:1])[CH3:35])=[O:6])[CH:10]=[CH:11][C:12]=2[N:17]=1
Reactant: COc1ccc(C[C@H](Nc2nc3ccc(CNC(=O)OC(C)(C)C)c(C)c3c(=O)o2)C(=O)O)cc1
Reactant: NC(=O)N1CCOCC1
Product: Cc1c(CNC(=O)OC(C)(C)C)ccc2nc(N[C@@H](C)C(=O)N(C)C)oc(=O)c12

Procedure:
N-[6-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl]-O-methyl-L-tyrosine, morpholineamide;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.7 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (0.1 g, 0.68 mmol) in DMF (20 ml) were added K2CO3 (0.19 g, 1.36 mmol, 2 eq.) and (bromomethyl)cyclopropane (92 mg, 0.68 mmol, 1 eq.). The mixture was stirred at RT for 4 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off to afford the crude product (0.15 g).