Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>C1C=CC=CC=1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:11]2[CH:12]=[N:13][CH:14]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Oc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-aminophenol (Aldrich; 1.0 equiv.) in benzene (1 M) was added 3-pyridenecarboxaldehyde (Aldrich; 1.0 equiv.). The flask was fitted with a Dean-Stark trap and heated to reflux overnight. (A solid mass formed on the bottom of the flask, which was difficult to break up). The reaction was cooled to ambient and concentrated in vacuo. The solid was taken up in methanol (0.2 M), cooled to 0° C., and treated with sodium borohydride (1.5 equiv.) in 4 portions. The cooling bath was removed and stirring continued for 2 hours. A small amount of was added to quench unreacted hydride. The reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude solid was recrystallized from hexanes/ethyl acetate to give N-(4-hydroxyphenyl)pyridin-3-ylmethylamine. 1H NMR (400 MHz, DMSO d6) 4.16 (2H, s), 6.41 (2H, m), 6.48 (2H, m), 7.28 (1H, ddd, J=0.73, 4.8, 7.7 Hz), 7.7 (1H, td, J=2.2, 7.3 Hz), 8.38 (1H, m), 8.39 (1H, s), 8.52 (1H, d, J=1.5 Hz).
Reaction SMILES: O.[O:2]1CCCC1.[CH3:7][C:8]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:9][C:10](=[O:13])[CH2:11][CH3:12].[BH4-].[Na+]>[OH-].[Na+]>[OH:2][C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:24])[CH2:16][CH:15]=[CH:14][C:8]([CH3:7])=[CH:9][C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Reaction time: 0.33 h

Procedure:
To a mixture of 1.9 g. of mercuric acetate, 6 ml. of water and 20 ml. of tetrahydrofuran is added 1.49 g. of 5,9,13-trimethyltetradeca-4,6,12-trien-3-one slowly. After addition is complete, the reaction mixture is stirred for about 20 minutes. The mixture is cooled to about 0° and 6 ml. of aqueous sodium hydroxide (3 molar) is added followed by 0.49 g. of sodium borohydride in aqueous sodium hydroxide (about 3 molar). The mixture is stirred for about 30 minutes. The mixture is then decanted, concentrated, diluted with water and then extracted with ether. The ethereal extract is washed with water, dried over magnesium sulfate and the product chromatographed on silica to yield 13-hydroxy-5,9,13-trimethyltetradeca-4,6-dien-3-one.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[NH:6][C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]1[N:29]=[C:28]([CH2:30][S:31]([CH:34]2[CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH:27]=[C:26]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]2[CH3:43])[N:25]=1>CN(C=O)C.COCCOC.C(O)C.O.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>[CH:1]1([NH:4][C:5](=[O:16])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:24]3[N:29]=[C:28]([CH2:30][S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:32])=[O:33])[CH:27]=[C:26]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]4[CH3:43])[N:25]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(Cl)n1
Reactant: O=C(Nc1ccc(B(O)O)cc1)NC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 100 °C

Procedure:
[4-(3-Cyclopropylureido)phenyl]boronic acid, pinacol ester (80 mg, 0.26 mmol), sodium carbonate (1.055 mL, 2.11 mmol), dichlorobis(triphenylphosphine)palladium(II) (14.8 mg, 0.02 mmol) and 2-chloro-4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (70 mg, 0.21 mmol) were suspended in 18% DMF in DME:Ethanol:Water 7:2:3 mixture (4 mL) and sealed into a microwave tube. The reaction was heated to 100° C. for 10 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol. The crude product was further purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a colourless gum (33.0 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:21]1([C:19]2[CH:20]=[C:16]([C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([CH:4]4[CH2:5][CH2:6][N:1]([C:28]5[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=5)[CH2:2][CH2:3]4)=[CH:8][CH:9]=3)=[O:15])[S:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1cc(-c2ccccc2)cs1
Reactant: O=C(O)c1ccc(F)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4cc(-c5ccccc5)cs4)cc3)CC2)nc1
Temperature: 175 °C
Yield: 47.1 %

Procedure:
A mixture of 4-phenyl-thiophene-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (141 mg, 1 mmol) in dioxane (3 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate (containing THF and methanol) and 0.2N hydrochloric acid. The organic layer was dried and evaporated. The residue was crystallized from methanol and ethyl acetate to give a pale yellow solid as 4-{4-[(4-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (114 mg). LC-MS for C28H25N3O3S (in/e) calcd 483, obsd 484 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH:8]([CH3:28])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=1)=[O:10])([CH3:3])[CH3:2].O.Cl>C(#N)C.[OH-].[Na+]>[CH:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH:8]([CH3:28])[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1)=[O:10])([CH3:2])[CH3:3]
Reactant: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC#CC(CC(=O)O)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Yield: 37 %

Procedure:
A solution of 156 mg of ethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}-hex-4-ynoate in 7 ml of acetonitrile and 7 ml of 1 N NaOH (aq) was stirred at room temperature for 18 h. The reaction mixture was admixed with water and adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 109 mg of 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoic acid in 37% yield over the two stages.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1cc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnn(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-methyl-1H-pyrazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:15][CH2:14][C:13]([NH2:17])=[O:16])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: C=CC(N)=O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: CO
Product: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reaction time: 40 h
Yield: 98.2 %

Procedure:
4-Bromo-2-trifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol (1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate (25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z=330.0, 328.0 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 6.92 (bs, 1H), 7.37 (bs, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](Cl)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]5[CH3:32])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:33]1(NC(C2C3C=C(C4C(C)=CN=C(Cl)N=4)SC=3C=CC=2)=O)CC1.C(OC(N1CCN(CCN)[C@H](C)C1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:33])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]5[CH3:32])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCN
Product: Cc1cnc(NCCN2CCNC[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of (R)-2-{5-chloro-2-[2-(2-methylpiperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (R)-4-(2-aminoethyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 451 [M+H].
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CN(C)[CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])=[O:12].CI.O>CS(C)=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:1])[S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CN(C)CCS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: C=CS(=O)(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h
Yield: 92.9 %

Procedure:
0.49 g (4.4 mmol) of potassium tert.butoxide are added at ambient temperature to a solution of 1.1 g (4 mmol) of 4-(2-dimethylamino-ethylsulphonylamino)-nitrobenzene (Example 379a) in 20 ml of DMSO. After 1.5 hours stirring 0.85 g (6 mmol) of methyl iodide are added. The mixture is stirred for 18 hours, then the reaction solution is poured into water and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and the solvent is eliminated in vacuo. 0.9 g of ethenesulphonic acid-N-(4-nitrophenyl)-N-methyl-amide are obtained as a crude product. 0.75 g of this crude product are dissolved in ethanol and combined with an excess of dimethylamine. After 18 hours stirring the mixture is evaporated to dryness.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[CH3:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: Cc1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)c2[nH]ccc2c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.68 g of 7-bromo-5-methyl-indole (8 mmol) were dissolved in 30 ml THF and 15 ml of a 1.6 molar solution of n-BuLi in hexane were added at −78° C. The reaction mixture was then allowed to warm to 0-5° C. and was stirred at this temperature for 30 min. Then it was cooled again to −78° C., dry ice was added and the mixture was allowed to warm to rt. After 15 min at rt it was poured into water and extracted twice with ether. The aqueous phase was then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were then washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with n-hexane. Final filtration yielded 0.78 g (56%) of 5-methyl-1H-indole-7-carboxylic acid as light brown solid. 1H NMR (DMSO-d, 300 MHz): δ 2.41 (s, 3H), 6.44 (m, 1H), 7.31 (m, 1H), 7.58 (s, 1H), 7.61 (s, 1H), 10.91 (br s, 1H), 12.92 (br s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]([NH:10][CH:11]([C:13]1[N:18]=[N:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[N:15][CH:14]=1)[CH3:12])=O)=[O:4].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:17]2)=[C:11]([CH3:12])[N:10]=1)=[O:4]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(C)(C)C)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4NC(=O)C(C)(C)C)n3n2)cc(OC)c1OC
Yield: 9.9 %

Procedure:
In a similar manner as described for Example 1, 2-[(2,2-dimethylpropanoyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 15) (0.040 g, 0.080 mmol) in 1,2-dichloroethane (10 mL) and phosphorus oxychloride (0.060 mL, 0.64 mmol) gave 2,2-dimethyl-N-(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)propanamide (0.0039 g) as a yellow solid. 1H NMR (CDCl3): δ8.87 (s, 1H), 8.66 (dd, J=8.6, 1.2 Hz, 1H), 8.62 (dd, J=8.1, 1.6 Hz, 1H), 7.43-7.37 (m, 1H), 7.16-7.11 (m, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 6.87 (s, 2H), 3.84 (s, 3H), 3.77 (s, 6H), 2.62 (s, 3H), 1.34 (s, 9H). MS m/z 491 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15](OC)=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([N:27]([CH3:28])[CH3:26])=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: CNC
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Product: CN(C)C(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
This compound was prepared from 700 mg. (1.99 mmol) of the end product of Example 9 and dimethylamine according to a procedure similar to that described above in Example 11. The reaction mixture was heated to 60°-65° in a sealed glass bomb for 16 hours. Recrystallization from acetone/ether/hexane yielded the desired end product: mp 176°-178°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([N:73]1[CH2:77][CH2:76][C@@H:75]([NH2:78])[CH2:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:66]([N:73]1[CH2:77][CH2:76][C@@H:75]([NH:78][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:74]1)[C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.021 g (0.12 mmole) of (R)-1-Benzyl-pyrrolidin-3-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.052 g of N—((R)-1-benzyl-pyrrolidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][CH:9]([CH2:22]Br)[S:8]1)=[O:5])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C1SC(CBr)CN1c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 64 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-bromomethylthiazolidine (0.7 g) and potassium t-butoxide (0.25 g) in t-butanol (30 ml) was refluxed for 5 hours. After removal of the solvent under reduced pressure, the concentrated residue was extracted with chlorofom (100 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure,-and the residue was subjected to column chromatography to give 0.36 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 1).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([O:16]CC)=O)[CH:8]=2)[NH:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[N:29]O)[NH2:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[N:28]=[C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]4)[O:16][N:29]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OCc3nc(Cc4ccc(Cl)cc4)no3)ccc2N1
Temperature: 110 °C
Yield: 27 %

Procedure:
To a stirred solution of ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (0.1 g, 0.4 mmol) in dry toluene (2 mL), 2-(4-chlorophenyl)-N′-hydroxyacetimidamide (0.073 g, 0.4 mmol) and potassium carbonate (0.1 g, 8 mmol) were added and heated to 110° C. in a microwave oven for 30 min. Solvent was removed under vacuum. Water (5 mL) was added to the residue, and the solid which formed was filtered, dried, and recrystallized using a mixture of ACN/Ethanol to afford 6-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off-white solid (40 mg, 27%). 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=7.60 Hz, 2H), 4.14 (s, 2H), 5.39 (s, 2H), 6.78-6.83 (m, 2H), 6.89 (d, J=2.40 Hz, 1H), 7.33 (d, J=8.40 Hz, 2H), 7.40 (d, J=8.40 Hz, 2H), 9.95 (s, 1H). LCMS: RT 1.85 min. LCMS (ES-API), m/z 370.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:25]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[N:38]1([CH2:37][CH2:36][CH2:35][NH:34][C:22]([C:19]2([CH2:18][CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:10]4[C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:25][C:7]=5[S:8][CH:9]=4)[CH2:12][CH2:13]3)[CH2:20][CH2:21]2)=[O:24])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCn1ccnc1)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Yield: 38 %

Procedure:
A suspension of 0.17 g (0.39 mmol) of 1-{2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid in 10 mL dichloromethane under nitrogen was treated with 1 mL of oxalyl chloride followed by 3 drops of DMF. After 2 hours the reaction was concentrated to a slurry, diluted with 10 mL DMF and treated with 0.10 g (0.78 mmol) of 1-(3-aminopropyl)imidazole followed by 0.12 g (1.2 mmol) of triethylamine. After 12 hours the reaction was poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to deliver an oil. Chromatographic purification gave 0.075 g (38%) of the desired final product as an oil.