Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[NH2:36][C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.C(C1C=C(N=C=S)C=CC=1)#N>>[C:37]([C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: N#Cc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C#N)c4)cc3)cc2C1=O

Procedure:
The compound of example 69 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-cyanophenyl isothiocyanate. The compound of example 69 was used directly without isolation for the preparation of compound of example 70.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:14]([NH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39](=[O:43])[O:40]2)=[CH:35][CH:34]=1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1.16 g (5 mmol) of Boc-L-leucine and 0.70 ml (5 mmol) of triethylamine in 12 mL of tetrahydrofuran (dried over sodium/lead alloy) at -15° was added 0.66 mL (5 mmol) of i-butyl chloroformate. After 10 min., 1.19 g (5 mmol) of 7-amino-3-phenylcoumarin suspended in 6 mL of tetrahydrofuran was added. The mixture was stirred at -15° for 30 min. and then overnight at room temperature. The reaction mixture was then reduced to dryness on a rotary evaporator at 1.6 kPa and 60°. The residue was taken up in 100 mL of ethyl acetate, washed twice with 25-mL portions of 1 N aqueous sodium bicarbonate and twice with 25-mL portions of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was dried overnight at room temperature and 3 Pa to yield 1.91 g. (84.8%) of crude product as a yellow foam which was purified by chromatography on a silica gel column eluted first with methylene chloride and then with 5% methanol in methylene chloride. Product recovery was 66.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(Br)ccn12
Temperature: 60 °C

Procedure:
Ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (step 2) (30.81 g, 114 mmol) in MeOH (172 ml) was treated with 2M NaOH (172 ml, 343 mmol) and the mixture was heated to 60° C. for 40 minutes.The volatile solvent was removed in vacuo and the crude material was treated with 2M sodium bisulfate solution to adjust the pH to 6-7. The resulting solid was collected by filtrationand added to water (400 ml). The mixture was stirred and heated to 90° C. for 1 h. After cooling to RT, the suspension was filtered and dried in a vacuum over at 40° C. to afford the title product;
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[C:12]([NH:14][C:15]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19]C(C)(C)C)=[O:18])=[O:13]>>[Br:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[C:12]([NH:14][C:15]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:16]=1[C:17]([OH:19])=[O:18])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(Br)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(3-bromobenzamido)-4-phenoxybenzoate and stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 31 mg of 2-(3-bromobenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(N(CC)CC)C.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][N:16]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CNCC4C3)cc12
Reactant: CN(C)C(=O)CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)N(C)C)CC4C3)cc12

Procedure:
A mixture of Example 282A (80.0 mg, 0.182 mmol), 2-chloro-N,N-dimethylacetamide (0.021 mL, 0.209 mmol), and triethylamine (0.127 mL, 0.908 mmol) in N,N-dimethylformamide (2 mL) was heated at 75° C. for 4 hours. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified by HPLC (same protocol as Example 221). The trifluoroacetic acid salt was flushed through an SCX column eluting with 2M ammonia in methanol to give the free base of the title compound. 1H NMR (400 MHz, Pyridine-d5) δ 2.58-3.06 (m, 13H), 3.31 (d, J=5.4 Hz, 2H), 3.39-3.44 (m, 1H), 3.71 (s, 3H), 6.43 (bs, 1H), 6.48 (bs, 1H), 7.12 (dd, J=9.1, 4.5 Hz, 1H), 7.27-7.36 (m, 1H), 7.50 (d, J=8.8 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 13.13 (bs, 1H). MS (ESI+) m/z 453.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.C(C1C=CC2OC(C)(C)[C@H](O)[C@@H](N(CC(OCC)=O)C3C=CC=CC=3)C=2C=1)#N.[NH2:44][C:45]1[S:46][CH:47]=[C:48]([CH3:50])[N:49]=1>>[OH:8][C@@H:7]1[C@@H:6]([NH:44][C:45]2[S:46][CH:47]=[C:48]([CH3:50])[N:49]=2)[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: Cc1csc(N)n1
Agent: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Product: Cc1csc(N[C@H]2c3cc(C#N)ccc3OC(C)(C)[C@@H]2O)n1

Procedure:
The title compound was prepared from (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (the title A compound of Example 3) and 2-amino-4-methyl-thiazole by the procedure described for the title compound of Example 1. The residue was purified by a flash column to give a colorless solid (730 mg, 58%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH:16]([C:18]([NH:20][CH3:21])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[C:7]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:17][CH:16]([CH2:18][NH:20][CH3:21])[CH2:15]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a suspension of 3.2 g (85 mmole) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise, a solution of 8.5 g (28 mmole) of 1-diphenylmethyl-N-methyl-3-azetidinecarboxamide in 50 ml of dry tetrahydrofuran. After the addition was complete, the reaction was refluxed for two hours, cooled to room temperature, and decomposed by the successive addition of 3.4 ml of water, 3.4 ml of 15% aqueous sodium hydroxide and 10.2 ml of water, titrating the final water addition to give a granular precipitate. The inorganic precipitate was removed by filtration, washed with tetrahydrofuran, and evaporated in vacuo. The residue was dissolved in chloroform, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 7.0 g of 1-(diphenylmethyl)-N-methyl-3-azetidinemethanamine as a heavy syrup. This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C:28](=[O:29])[C:27]([CH3:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:26][C:25]2=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[H-].[Na+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].Cl>CN(C=O)C.C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C:28](=[O:29])[C:27]([CH3:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:25]2=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)NC(C)(c3ccccc3)C2=O)c1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)N(CC(=O)OC)C(C)(c3ccccc3)C2=O)c1
Reaction time: 0.67 h

Procedure:
To [6-methoxy-2′-(4-methyl-2,5-dioxo-4-phenyl-imidazolidin-1-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.087 g, 0.16 mmol) in DMF (0.9 mL) was added sodium hydride (60% in mineral oil; 0.013 g, 0.20 mmol), followed by methyl bromoacetate (0.02 mL, 0.18 mmol), and the reaction was stirred for 40 minutes. The mixture was worked-up with H2O, CH2Cl2, and 1N aqueous HCl, and then purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]23[CH2:14][N:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[O:3][C:4]([C:7]23[CH2:14][N:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=1)(=[O:17])[CH3:16]
Reactant: Nc1ncc(C23CCCN(CC2)C3)o1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ncc(C23CCCN(CC2)C3)o1
Yield: 60 %

Procedure:
A solution of (±)5-(2-amino-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane (E3) (0.25g, 1.3 mmole) in acetic anhydride (8 ml) was refluxed for 1h under nitrogen. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous potassium carbonate solution (10 ml). After extraction into chloroform (3×10 ml) the organic extracts were dried over sodium sulphate and concentrated in vacuo. Trituration of the resulting gum with ether afforded the title compound (E14) as a solid (180 mg, 60%) m.p. 142°-143° C. (from methanol-ether).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.FC1C=CC(CN2CCN(C(CNS(C3C=CC(OCC4C5C(=CC=CC=5)N=C(C)C=4)=CC=3)(=O)=O)C([O-])=O)CC2)=CC=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C@@H:6]([CH2:5][NH:4][S:45]([C:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:26])[CH:36]=4)=[CH:40][CH:41]=3)(=[O:46])=[O:47])[C:7]([O:9][CH3:10])=[O:8])[CH2:16][CH2:15]2)=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cc1cc(COc2ccc(S(=O)(=O)NCC(C(=O)[O-])N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydro chloride and 1.6 g (4.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in 17.2), 1.0 g (46%) of methyl (S)-2-[4-(4-fluorobenzyl)piperazin-1-yl-3-(4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CC(C)S(N)(=O)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) and propane-2-sulfonamide as described in Example 181, Step A. MS (ESI) m/z=551 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH2:41][N:42]([CH3:44])[CH3:43])[C:5]([NH:7][C@H:8]([B:25]1[O:33][CH:32]2[C:27]([CH3:37])([CH:28]3[CH2:34][CH:30]([CH2:31]2)[C:29]3([CH3:36])[CH3:35])[O:26]1)[CH2:9][C:10]1[C:11]([O:23][CH3:24])=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].[CH2:45]([O:52][C:53]([NH:55][C@@H:56]([CH2:60][NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:57](O)=[O:58])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C.O>[CH2:45]([O:52][C:53]([NH:55][C@@H:56]([CH2:60][NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:57]([NH:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[CH2:41][N:42]([CH3:43])[CH3:44])[C:5]([NH:7][C@H:8]([B:25]1[O:33][CH:32]2[C:27]([CH3:37])([CH:28]3[CH2:34][CH:30]([CH2:31]2)[C:29]3([CH3:35])[CH3:36])[O:26]1)[CH2:9][C:10]1[C:11]([O:23][CH3:24])=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:6])=[O:58])=[O:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(N)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(3-amino-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate from step 3 in Example 18 (130 mg, 0.22 mol) and (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoic acid (85 mg, 0.25 mol) in DCM/DMF (4 mL, 1/1) was added NMM (1.2 eq) followed by HATU (114 mg, 0.3 mol). The reaction mixture was stirred overnight at rt. Water was added and the aqueous phase extracted with EtOAc. The organic phase was washed with 1N HCl, sat. NaHCO3, brine, dried and concentrated in vacuo to afford the product (0.130 g) as a brown oil. ESI-MS m/z 926.1 (MH)+.
Reaction SMILES: F[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[NH:3]1.C(O)(=O)CCC(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:4]1[N:3]=[N:2][C:7]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:21][CH2:22]2)=[CH:6][CH:5]=1
Reactant: FC1=CC=CN(F)N1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCC2CCN(c3ccc(F)nn3)CC2)cc1
Yield: 64.3 %

Procedure:
A mixture 1.2 parts of 2,6-difluoropyridazine, 4 parts of ethyl 4-[2-(4-piperidinyl)-ethoxy]benzoate butanedioate(1:1), 5.3 parts of sodium carbonate and 141 parts of N,N-dimethylformamide was stirred for 48 hours at 60° C. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.4 parts (64.3%) of ethyl 4-[2-[1-(6-fluoro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 131.9° C. (comp. 73).
Reaction SMILES: C=CC=C.[CH2:5]([C:7]1([CH2:24][CH3:25])[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:9]=[CH:8]1)[CH3:6]>>[CH2:24]([C:7]1([CH2:5][CH3:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:9]=[CH:8]1)[CH3:25]
Reactant: CCC(CC)C1CC=CCCC=CCC(CC)(CC)C=N1
Agent: C=CC=C
Product: CCC(CC)C1CCCCCCCCC(CC)(CC)C=N1

Procedure:
Reaction of 1-(3-pentyl)-4,4-diethyl-2-aza-1,3-butadiene [produced by reaction of 2-ethylbutyraldehyde with ammonia according to U.S. Pat. No. 2,319,848] with 1,3-butadiene to 3,3-diethyl-12-(3-pentyl)-1-aza-1,5,9-cyclododecatriene (b.p. 90°-92° C./0.13 Pa; nD20 =1.4840), and hydrogenation to obtain 3,3-diethyl-12-(3-pentyl)-1-aza-cyclododecene; b.p. 95° C./4 Pa.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH2:14])=[NH:13])[CH2:2][CH3:3].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O1CCOCC1>[O:17]=[C:18]1[NH:14][C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[N:13][CH:25]=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccccc1NC(=N)N
Solvent: C1COCCO1
Product: CCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a solution of N-(2-propoxyphenyl)guanidine (9.1 g) in dioxane (30 ml) is added dropwise diethyl ethoxymethylenemalonate (10.2 g), and the mixture is refluxed with stirring for 5 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(2-propoxyanilino)-5-pyrimidinecarboxylate (11.7 g). M.p. 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6][N:7]([C:17](=[O:42])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[NH2:15].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[NH2:15])[C:17](=[O:42])[C:18]1[CH:19]=[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-carbamoyl-phenyl)-amino]-butyric acid methyl ester (0.031 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure to give the title compound (0.032 g) as a colourless gum.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1COCC1>CCOCC.[Zn]>[F:16][C:10]([F:17])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.00 mmol) in a solution of benzaldehyde (0.531 g, 5 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.522 g, 7.50 mmol) in an. THF (10 mL) was sonicated for 4-5 h and then stirred at rt overnight. The reaction was cooled and diluted with ether and washed with 1 N HCl, water, brine and dried (MgSO4). Evaporation of solvents afforded a clear oil which was purified by silica gel FCC (0-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate as a clear oil (619 mg, ˜54%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49-7.44 (m, 2H), 7.43-7.39 (m, 3H), 5.23-5.12 (m, J=15.3, 8.0, 5.5 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.87-2.76 (m, 1H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 1.22 g. of benzoic acid, 1.62 g. of 1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 3 hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride was added. The reaction mixture was stirred for 18 hours, then heated at reflux for 5 hours, then diluted with 5 ml. of water and heated for an additional 30 minutes. The mixture was concentrated to remove most of the solvent and to the residue was added chloroform and 35 ml. of 1N sodium hydroxide. The layers were separated. The organic layer was washed with water, dried over magnesium sulfate, concentrated and diethyl ether was added, giving the desired product, m.p. 134°-136° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>>[C:23]([CH2:22][CH2:21][C:20]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:26])([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Product: Nc1nc(-c2ccccc2)c(CCOC(=O)CCC(=O)O)c2ncnn12

Procedure:
The title compound was prepared by the method of Example 2 using 2.5 g (0.01 mole) of the product compound of Example 1 and 1.0 g (0.01 mole) of succinic anhydride.