Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:43]=[C:42]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]=[CH2:52])=[CH:47][CH:46]=3)[C:41]([Cl:53])=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][O:39]3)[O:22][C@@H:21]1[CH2:54][O:55][C:56](=[O:58])[CH3:57])(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:43]=[C:42]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:2][CH2:52]4)=[CH:47][CH:46]=3)[C:41]([Cl:53])=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][O:39]3)[O:22][C@@H:21]1[CH2:54][O:55][C:56](=[O:58])[CH3:57])(=[O:18])[CH3:17]
Reactant: CC[Zn]CC
Reactant: C=Cc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3c(c2Cl)OCCC3)cc1
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
The mixture of Et2Zn (1.1 M in toluene, 4 mL, 4.39 mmol) and CH2Cl2 (8 mL) was cooled to 0° C. TFA ((0.34 mL, 4.39 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was stirred at 0° C. for 1 hr. CH2I2 ((0.36 mL, 4.39 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was stirred at 0° C. for 1 hr. The acetate 179 ((270 mg, 0.44 mmol) in CH2Cl2 (4 mL)) was added to the mixture at 0° C. The mixture was warmed up to rt slowly and stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/aq. sat'd NH4Cl (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the title product 180 (152 mg, 55%).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:11][N:10]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH:24]12[CH2:32][CH:28]([CH2:29][NH:30][CH2:31]1)[CH2:27][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25]2>C(O)(C)C>[CH2:15]([O:14][C:12]([NH:10][CH:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)[CH2:11][N:30]1[CH2:31][CH:24]2[CH2:32][CH:28]([CH2:27][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25]2)[CH2:29]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC2CN2C(=O)OCc2ccccc2)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(COc3ccc(C#N)cc3)NC(=O)OCc3ccccc3)C2)C1
Temperature: 60 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Benzyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (1.0 g; 3.2 mmol; from step (iii) above) was mixed with tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (v) above; 0.73 g; 3.2 mmol) and 30 mL of iso-propanol, and stirred at 60° C. for 5 h, and then at rt overnight. The solvent was evaporated and the crude material was purified on silica (DCM:5% MeOH) yielding 1.3 g (76%) of sub-title compound.
Reaction SMILES: Cl[C:2](=[N:10][N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23].CN(C)C1C=CC=CC=1.Cl>ClCCl>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]1[N:23]([C:22]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=2[CH3:20])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:10]=1
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1c(C)cccc1C
Temperature: 120 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
First, 12.6 g (43.3 mmol) of N-[1-chloro-1-(2-methylphenyl)methylidene]-N′-[1-chloro(1-phenyl)methylidene]hydrazine, 15.7 g (134.5 mmol) of 2,6-dimethylaniline, and 100 mL of N,N-dimethylaniline were put into a 500 mL recovery flask and heated and stirred at 120° C. for 20 hours. After reaction for a predetermined time, this reaction solution was slowly added to 200 mL of 1N hydrochloric acid. Dichloromethane was added to this solution and a target substance was extracted to an organic layer. The obtained organic layer was washed with water and an aqueous solution of sodium hydrogen carbonate, and was dried with magnesium sulfate. The magnesium sulfate was removed by gravity filtration, and the obtained filtrate was concentrated to give a black liquid. This liquid was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and hexane in a ratio of 1:5 was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized from ethyl acetate to give 4.5 g of a white solid of Hmpptz-dmp in a yield of 31%. A synthetic scheme of Step 1 is shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:22]3[S:23][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:31])=[O:7])[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:18]=2)=[CH:41][CH:42]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 156. NMR (CDCl3): 2.57-2.59 (m, 4H, 2×CH2), 2.92 (s, 3H, CH3), 3.30-3.32 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.58 (m, 4H, 2×CH2), 3.85 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.67 (sbr, 2H, NH2), 6.58 (d, H, ArH, J=8.64 Hz), 7.29 (s, H, ArH), 8.48 (dd, H, ArH, J=2.2 Hz, 8.6 Hz), 9.17 (d, H, ArH, J=2.02 Hz). MS: (ESI+): MH+ 527.49
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1.[C-]#N.[Na+]>O.CO>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 1,4-benzodioxan-6-amine (170 mg, 1.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (206 mg, 1.2 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) and stirred at room temperature for 20 minutes. Work-up and purification afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine as a white solid (245 mg, 71% over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=[C:6]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:5]=12)[CH2:2][CH3:3].[Cl:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[ClH:19].[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:5]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15]1)=[O:21])[CH3:24]
Reactant: CCCc1c2c(nc3ccccc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCCc1c2c(nc3ccccc13)CCN(C(=O)OCC)CC2
Product: Cl
Yield: 84 %

Procedure:
1,2,4,5-Tetrahydro-11-propyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-propyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9](=[O:12])[CH2:10][CH3:11].[OH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:28][CH:27]=1)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCC(=O)C(CCCCCCBr)C(=O)CC
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC(C(=O)CC)C(=O)CC)cc1

Procedure:
A mixture of 26.3 g. (0.0758 mole) of 4-(6-bromohexyl)-3,5-heptanedione, 13.1 g. (0.0787 mole) of ethyl p-hydroxybenzoate, 31.5 g. (0.228 mole) of powdered potassium carbonate, 4 g. of potassium iodide and 500 ml. of acetone was heated at reflux for 36 hours. The reaction mixture was concentrated in vacuo and partitioned between water and methylene dichloride. The organic layer was washed successively with sodium hydroxide solution, water, hydrochloric acid, water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated and the residue crystallized and recrystallized from n-pentane to give 4-[10-(4-carbethoxyphenoxy)decyl]-3,5-heptanedione, m.p. 45°-46° C.
Reaction SMILES: [Na].[CH3:2][NH:3][CH:4](O)[CH3:5].[C:7]1([C:13]([C:32]([F:35])([F:34])[F:33])=[C:14]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC[O:38]CC>>[C:7]1([C:13]([C:32]([F:33])([F:34])[F:35])=[C:14]([C:25]2[CH:26]=[CH:27][C:28]([O:38][CH2:5][CH2:4][NH:3][CH3:2])=[CH:29][CH:30]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: CCOCC
Reactant: CNC(C)O
Agent: [Na]
Product: CNCCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCOC)cc2)cc1
Temperature: 150 °C
Yield: 72.4 %

Procedure:
0.28 g (0.012 g.-atoms) of sodium are dissolved in 2.70 g (36 mmoles) of N-methylamino-ethanol, 2.36 g (5.86 mmoles) of 2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-1-(4-methoxymethoxy-phenyl)-propene, prepared as described in Example 33, are added, and the mixture is heated at 150° C. for one hour. The mixture is cooled, diluted with 100 ml of ether, washed with water until neutral, dried and evaporated. The residue is crystallized from hexane. 1.94 g (72.4%) of 2-phenyl-3,3,3-trifluoro-1-[4-(2-methylaminoethoxy)-phenyl]-1-(4-methoxymethoxy-phenyl)-propene are obtained; m.p.: 87°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#Cc1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#Cc3ccccn3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 2-ethynylpyridine under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The fractions homogenous by TLC were combined and evaporated. Crystallization of the residue from ethyl acetate and recrystallization from tetrahydrofuran/methanol gave off-white crystals of 4-(2-chlorophenyl)-9-methyl-2-[2-(2-pyridinyl)-ethynyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 153°-155°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C1([Li])C=CC=CC=1.[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:25][CH2:24]1)#[N:22]>C1C=CC=CC=1.C(OCC)C>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[N:1]=[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[O:30])[CH2:27][CH2:28]2)[N:22]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: N#CN1CCN(C(=O)c2ccco2)CC1
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Reaction time: 0.75 h

Procedure:
To 3.6 g. of 6-aminoveratronitrile, dissolved in 75 ml. of anhydrous benzene, a solution of phenyl lithium (prepared from 0.35 g. of lithium and 3.9 g. of bromobenzene) in 60 ml. of anhydrous diethyl ether is added under a nitrogen atmosphere. After 45 minutes 4.4 g. of 1-cyano-4-(2-furoyl)piperazine in 50 ml. of anhydrous benzene are added. The ether and part of the benzene are distilled off and 100 ml. of tetrahydrofuran are added. The mixture is refluxed under the nitrogen atmosphere for 20 hours and then decomposed with water. The liquid is distilled off and 75 ml. of water are added to the residue. The mixture is extracted with chloroform and the extract is concentrated by evaporation of the solvent. 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)4-(2-furoyl)piperazine is obtained. The product after crystallization from a mixture of ethanol and water melts at 258°-260°C.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(0.005 mol.) of 2-(4-hydroxybenzoyl)-3-phenylbenzofuran with 2.7 g. (0.02 mol.) of 2-diethylaminoethyl chloride in 50 ml. of acetone containing 2.7 g. (0.02 mol.) of potassium carbonate for three hours according to the procedure described in Example 1 gives the title compound.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=4[O:43][CH3:44])[N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:45])[C:8]([CH3:46])=[CH:7]1)C.C1COCC1.O[Li].O>CO>[CH2:41]([O:40][P:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:19]2[N:18]=[C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:10]=3[C:9](=[O:45])[C:8]([CH3:46])=[CH:7][N:6]4[CH2:5][C:4]([OH:47])=[O:3])[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][N:20]=2)=[C:29]([O:43][CH3:44])[CH:30]=1)([O:37][CH2:38][CH3:39])=[O:36])[CH3:42]
Reactant: CCOC(=O)Cn1cc(C)c(=O)c2c(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)cccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3c(=O)c(C)cn4CC(=O)O)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A solution of ethyl[5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxoquinolin-1(4H)-yl]acetate (Example 300, 41 mg, 0.061 mmol) in MeOH (0.5 mL), and THF (0.5 mL) was charged with LiOH H2O (25.6 mg, 0.61 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The material was purified by prep TLC (5% MeOH in DCM) to give 24.1 mg of the desired product (yield: 61%). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (m, 6H), 1.99 (s, 3H), 3.24 (d, J=21.2 Hz, 2H), 3.78 (s, 3H), 3.99 (m, 2H), 6.90 (d, 1H), 7.03 (s, 1H), 7.43 (s, br, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.94 (s, br, 1H). 8.36 (s, 1H), 8.51-8.56 (m, 2H). MS (ES+): m/z 651.19 [MH+]. HPLC: tR=1.32 min (UPLC TOF, polar—3 min).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34]Br)=[O:18])[CH3:15].[Br-]>C(#N)C>[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Phenol (0.518 g, 5.5 mmol) is combined with anhydrous acetonitrile (20 mL) and cesium carbonate (2.3 g, 10 mmol) and allowed to stir at room temperature under nitrogen. To the reaction is added 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.97 g, 5.00 mmol). The reaction is monitored by TLC until all of the bromide is consumed. The reaction is diluted with ethyl ether (100 mL), then o.1N NaOH (50 mL) is added. The two phases are separated, then the organic layer is washed with water (50 mL) and brine (50 mL). The organic layer is dried over anhydrous sodium sulfate, then concentrated. The material is further purified using flash chromatography to yield 1.75 g or 86% yield of the product.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]2([CH3:15])[CH:6]1[CH2:7][CH2:8][C:9]2=[O:16])[CH:2]=C.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:15][C:10]12[C:9](=[O:16])[CH2:8][CH2:7][CH:6]1[CH:5]([O:4][CH2:1][CH:2]=[O:26])[C:13](=[O:14])[CH2:12][CH2:11]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1C(=O)CCC2(C)C(=O)CCC12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC12CCC(=O)C(OCC=O)C1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A commercial 4% w/w solution of osmium tetraoxide (10 mL, 0.82 mmol, 0.005 eq) was added to a stirred mixture of 4-allyloxy-7a-methyl-hexahydro-indene-1,5-dione (36.4 g, 164 mmol), 2,6-lutidine (57.2 mL, 246 mmol, 1.5 eq) and sodium periodate (210.6 g, 492 mmol, 3 eq) in dioxane (900 mL) and water (300 mL) at 0° C. The reaction mixture was then allowed to warm slowly to room temperature, and stirred for 24 h. The reaction mixture was cooled to 0° C., and then filtered through a fritted funnel. DCM (1 L) was used to wash to salt cake, and the filtrate was used to extract the separated aqueous solution (4×250 mL). The combined organic layer was dried with magnesium sulfate. The resulting mixture was filtered, condensed and the resulting residue purified by flash chromatography using 20-90% ethyl acetate in hexane yield the title compound as a light yellow foam.
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(Cl)OC1CCCCC1
Reactant: [F-]
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: O=C(F)OC1CCCCC1
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
The preparation was carried out as in Example 2 but using 250 g of ethylene carbonate, 90 g (1.55 mol) of potassium fluoride and 162.6 g (1.0 mol) of cyclohexyl chloroformate. After addition of the chloroformate, stirring of the mixture was continued for 45 minutes at 45° C. Evaporation under vacuum was carried out as above. By distillation under reduced pressure, 122.7 g (84% yield) of cyclohexyl fluoroformate with a boiling point of 55-56° C. at 22 mm Hg were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:51]([CH3:62])[CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1COCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:27])[CH:29]=[CH:30][CH:31]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cccc(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (69 mg), 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (60 mg), HBTU (68 mg) and diisopropyl ethyl amine (112.5 μL) in DCM (5 mL) and THF (1 mL) were stirred at room temperature overnight. It was concentrated. Separation via CombiFlash then afforded the desired product (33 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([OH:23])[C:20]([NH2:22])=[O:21].O[NH-].O=[N-]>>[NH2:22][C:20](=[O:21])[C:19](=[O:23])[CH:18]([NH:17][C:14]([C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
Coupling of (S)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide was followed by oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: O.[CH3:2][NH:3][CH2:4][CH2:5][NH:6][CH3:7].[NH2:8][C:9]1[C:10](Cl)=[C:11](Cl)[C:12](=[O:16])[N:13]([CH3:15])[N:14]=1.C(Cl)(Cl)Cl>CO>[NH2:8][C:9]1[C:10]2[N:3]([CH3:2])[CH2:4][CH2:5][N:6]([CH3:7])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[N:14]=1
Reactant: Cn1nc(N)c(Cl)c(Cl)c1=O
Reactant: CNCCNC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCN(C)c2c1c(N)nn(C)c2=O
Yield: 82.3 %

Procedure:
Water (9 ml) and N,N'-dimethylethylenediamine (0.8 ml, 7.7 mmol) were added to 6-amino-4,5-dichloro-2-methyl-3(2H)-pyridazinone (500 mg, 2.6 mmol) as described in Chemical Pharmaceutical Bulletin, 30, 832 (1982), and the mixture was refluxed under heating for 3 hours. The reaction mixture was concentrated, added with chloroform, washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was subjected to silica gel column chromatography (chloroform:methanol=40:1) to give 448 mg of 8-amino-1,2,3,4-tetrahydro-1,4,6-trimethylpyrazino[2,3-d]pyridazin-5(6H)-one.