Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Yield: 36 %

Procedure:
The title compound is prepared in 36% yield (95 mg, clear pale yellow oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-17, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (103 mg, 0.74 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: O=[N+]([O-])O
Product: O=C1CCc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
86.0 g (0.51 mole) of 5-chloro-1-indanone are introduced in portions into 540 ml of fuming nitric acid (d=1.54), cooled to -20° C., so that the temperature of the reaction mixture remains between -10° and -15° C. After the addition has ended, the mixture is subsequently stirred for 45 minutes at -15° to -20° C., the reaction solution is poured onto ice and the precipitate which has separated out is filtered off and washed with water. The crude product of melting point 110°-113° is recrystallized from ethanol, whereby the melting point of the pure 5-chloro-6-nitro-1-indanone rises to 126°-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30]([CH2:31][CH3:32])[C:42]([NH:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:43])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:13]([O:15][P:16]([CH2:36][NH2:37])([CH2:18][CH:19]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH3:14]>>[CH2:13]([O:15][P:16]([CH2:36][N:37]1[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]1=[O:7])([CH2:18][CH:19]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH3:14]
Reactant: O=C1CCCC(=O)O1
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CCCC1=O
Yield: 27.9 %

Procedure:
In a manner analogous to that described in Example 24(A), from 0.161 g (1.41 mmol) of glutaric anhydride and 0.41 g (0.94 mmol) of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate, there was obtained 0.124 g of (glutarimidomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1>C1(C)C=CC=CC=1>[O:5]1[CH:6]=[CH:7][CH2:8][CH:9]([C:1]([Cl:4])=[O:2])[CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: C1=COCCC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CC=COC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 56709.5 %

Procedure:
125 g (1.25 mmol) of phosgene gas were introduced over the course of 2.5 hours at 45°-50° C. into a solution of 84 g (1 mol) of 5,6-dihydro-4H-pyran in 50 g of toluene. The mixture was subsequently stirred at 60° C. for a further 5 hours. Work-up was carried out as described in Example 1. Vacuum distillation at 76° C./1 mbar gave 103.9 g (80%) of valuable product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:11])[C:13](=[O:14])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1CCN(C(C)=O)CC1
Product: CC(=O)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Yield: 54 %

Procedure:
The amine obtained in Stage A is treated with benzyl chloroformate in accordance with the process described in Stage B of Example 1 to obtain the desired carbamate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][O:12][C:13]=2[NH2:14])=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([NH:14][C:13]1[O:12][N:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=1)=[O:22]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1oncc1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1oncc1-c1ccc(C(F)(F)F)cc1

Procedure:
4-(4-(Trifluoromethyl)phenyl)-5-aminoisoxazole (1.0 g) and 2,6-dimethoxybenzoylchloride (2 g) were refluxed in 100 ml. toluene for 3 hours. The reaction mixture was cooled and the final product was then collected and recrystallized from ethanol, m.p. 199°-201° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.CCOCC>[C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:26])=[O:1])[C:21]=2[CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc2c(c1)N(CCCCCCO)c1ccccc1S2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)N(CCCCCC(=O)O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
A solution of 41 mg (0.12 mmol) of 1-[10-(6-hydroxyhexyl)-10H-phenothiazin-2-yl]ethanone in 0.16 mL of N,N-dimethylformamide is treated with 158 mg (0.42 mmol) of pyridinium dichromate and stirred at room temperature for 12 hours. The mixture is diluted with ether and filtered through a pad of celite with the aid of 100 mL of ether. The filtrate is washed successively with 10% sodium bisulfate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to give 10 mg (23%) of 2-acetyl-10H-phenothiazine-10-hexanoic acid as a dark residue. The 1 H NMR (300 MHz, CDCl3) is consistent with the desired product. MS (CI) m/e 323 (M+ +H).
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([OH:52])=O)[O:47][C:48]=1[CH3:49]>C(Cl)Cl>[CH3:43][C:44]1[CH:45]=[C:46]([C:50]([NH:2][NH2:3])=[O:52])[O:47][C:48]=1[CH3:49]
Reactant: Cc1cc(C(=O)O)oc1C
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NN)oc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl carbazate (350 mg, 2.65 mmol), HBTU (1.01 g, 2.66 mmol), and N,N-diisopropylethylamine (923 μL, 5.30 mmol) were added to a methylene chloride (5 mL) solution of commercially available 4,5-dimethylfurancarboxylic acid (248 mg, 1.77 mmol), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated, to the residue, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was subjected to extraction with methylene chloride and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was dissolved in methylene chloride (6 mL). To the solution, trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain 4,5-dimethylfuran-2-carbohydrazide.
Reaction SMILES: [BrH:1].C([NH:5][CH:6]1[CH2:15][CH2:14][C:9]2[N:10]=[C:11]([NH2:13])[S:12][C:8]=2[CH2:7]1)(=O)C>Br>[BrH:1].[BrH:1].[NH2:13][C:11]1[S:12][C:8]2[CH2:7][CH:6]([NH2:5])[CH2:15][CH2:14][C:9]=2[N:10]=1
Reactant: CC(=O)NC1CCc2nc(N)sc2C1
Agent: Br
Product: Nc1nc2c(s1)CC(N)CC2

Procedure:
3 g (0.01 Mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole-hydrobromide are dissolved in 20 ml of semi-concentrated hydrobromic acid and refluxed for 6 hours. The solution is then concentrated by evaporation and the residue recrystallised from methanol.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: CC(C)N1CCNCC1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Solvent: CCCCCO
Product: CC(C)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 130 °C

Procedure:
The mixture of 0.26 g (0.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.66 g (3.2 mmol) of 1-isopropylpiperazine in 6 ml of pentanol is heated in a sealed tube at 130° C. for 10 hours.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:3][CH2:4][C:6]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(CO)CCCC1
Yield: 5 %

Procedure:
1-Cyano-cyclopentanecarboxylic acid ethyl ester (2.00 g, 12.0 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under nitrogen and lithium aluminium hydride (36 ml, 36 mmoles, 1.0M in THF) was added dropwise at 0° C. After stirring at room temperature for 24 h water was carefully added to the reaction and the product mixture extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed with water (40 ml) and saturated sodium chloride solution (25 ml). The combined organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-hydroxymethyl-cyclopentanecarbonitrile (75 mg, 28%) as an oil which solidified on standing to give a waxy yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:5]=[C:4]2[CH2:21][CH2:22][CH2:23][C:3]=12.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1>>[OH:33][CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[N:5]=[C:4]3[CH2:21][CH2:22][CH2:23][C:3]=23)=[CH:26][CH:27]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c3c(n2)CCC3)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CCO)cc3)c3c(n2)CCC3)CC1
Yield: 39.5 %

Procedure:
Following general procedure B1, tert-butyl 4-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate (0.050 g, 0.15 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.030 g, 0.22 mmol) to afford the title compound (0.026 g, 40%) as an orange oil. MW=438.56. APCI MS m/z 439 [M+H]+.
Reaction SMILES: [NH:1]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.[CH2:29]([N:32]([CH2:49][CH:50]=[CH2:51])[C:33]1[N:38]=[C:37](Cl)[N:36]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:34]=1)[CH:30]=[CH2:31].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([N:1]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:37]2[N:38]=[C:33]([N:32]([CH2:49][CH:50]=[CH2:51])[CH2:29][CH:30]=[CH2:31])[N:34]=[C:35]([NH:40][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:42])[N:36]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CCN(CC=C)c1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCN(CC=C)c1nc(NC(C)(C)CC(C)(C)C)nc(N(CCCCCCN(c2nc(NC(C)(C)CC(C)(C)C)nc(N(CC=C)CC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Yield: 19.2 %

Procedure:
A stirred solution of 4,4'(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (9.5 grams; 0.024 mole), 2-diallylamino-4-chloro-6-t-octylamino-1,3,5-triazine (16.0 grams; 0.048 mole), and powdered sodium hydroxide (2.0 grams; 0.05 mole) in xylene (150 mls) is heated at reflux for 24 hours while removing by-product water by means of a trap. The resulting mixture is then filtered and the filtrate is heated to evaporate the solvent and obtain a light tan oil which solidifies on triturating with petroleum ether. The solid is then recovered and dried to obtain 4.6 grams of the desired product, mp 113115° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[C:24]([CH3:25])=[CH:23][S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[C:24]([CH3:25])=[CH:23][S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cscc1-c1ccccc1C(Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 150 °C
Yield: 38.1 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep HPLC to give 15.1 mg of (S)-2-amino-3-(4-{2-amino-6-[2,2,2-trifluro-1-(2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.94(d, J=8 Hz, 2H), 7.80(s, 1H), 7.50(m, 5H), 7.25(m, 2H), 7.03(s, 1H), 6.94(s, 1H), 4.31(t, J=5.6, 1H), 3.48(m, 1H), 3.26(m, 1H), 1.98(s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: CO
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(OC)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:6]=2[N:7]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[Cl:12][C:10]1[N:9]=[CH:8][C:6]2[N:7]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]3)[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]=2[CH:11]=1
Reactant: CCCOCCn1c(=O)c(Cl)nc2cnc(Cl)cc21
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOCCn1c(=O)c(N2CCN(CCO)CC2)nc2cnc(Cl)cc21
Yield: 83 %

Procedure:
A solution of 3,7-dichloro-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one (200 mg, 0.66 mmol), 1-(2-hydroxyethyl)piperazine (117 mg, 0.90 mmol, Aldrich) and triethylamine (0.27 mL, 1.94 mmol) in THF (3 mL) was stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give 7-chloro-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one. (218 mg, 83% yield). 1H NMR (CDCl3) δ 8.48 (1H), 7.34 (1H), 4.33-4.30 (2H), 4.04-4.00 (4H), 3.76-3.72 (2H), 3.69-3.65 (2H), 3.38-3.34 (2H), 2.67-2.64 (4H), 2.62-2.58 (2H), 1.55-1.48 (2H), 0.87-0.82 (3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH:25]2[CH2:27][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36](Cl)=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:29][CH:24]2[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[CH2:29][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36]([O:8][C:5]5[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=5[F:9])=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:27][CH:25]2[CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 149.6 %

Procedure:
4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (4.70 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 100%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 8.50 (s, 1H), 7.48 (s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, 1H), 6.48 (dd, 1H), 6.40 (dd, 1H), 5.40 (br s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 559.2, found 559.4.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])C.Br[C:40]1[CH:54]=[CH:53][C:43]([CH2:44][O:45][Si](C(C)(C)C)(C)C)=[C:42]([F:55])[CH:41]=1>>[F:55][C:42]1[CH:41]=[C:40]([C:34]2[CH:35]=[CH:36][C:31]([N:28]3[CH2:27][CH2:26][CH:25]([CH2:24][C:11]4[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:38])=[O:8])[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=4)[CH2:30][CH2:29]3)=[N:32][CH:33]=2)[CH:54]=[CH:53][C:43]=1[CH2:44][OH:45]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Br)cn3)CC2)nc(C)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1F
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)c(F)c4)cn3)CC2)nc(C(=O)NCC(=O)O)c1O
Yield: 21 %

Procedure:
In accordance with Examples 19-(2), 1-(10), 22-(4) and 1-(13), but using ethyl({[5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and [(4-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 21%) was afforded as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:34](O)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:42])[C:13]1=[O:43])(C(C)(C)C)(C)C.[CH:44](O)=[O:45]>CC(=O)OCC.O.[Zn]>[CH:44]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:33])[F:32])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:42])[C:13]1=[O:43])=[O:45]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Reactant: O=CO
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccccc3)c(-c3cccc(OC(F)(F)F)c3)ncc21
Temperature: 40 °C
Yield: 80 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-(hydroxy(phenyl)methyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.162 mmol) in HCOOH (2 mL) was added Zn dust (105 mg, 1.62 mmol). The reaction was heated at 40° C. for 6 h, cooled to RT then diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4, and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate, LCMS: MH+ 514 and TR=1.790 min and 3-(5-benzyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate, LCMS: MH+ 516 and TR=1.714 min, (66.7 mg, 80% yield) as an oil. Used without further purification.