Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C([N:17]1[C:21](=[O:22])[C:20]([CH:24]([CH3:26])[CH3:25])([CH3:23])[N:19]=[C:18]1[C:27]1[N:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=O)C1C=CC=CC=1.[Cl-].[NH4+]>CO>[CH:24]([C:20]1([CH3:23])[C:21](=[O:22])[NH:17][C:18]([C:27]2[N:36]=[CH:35][C:34]([CH2:37][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[N:19]1)([CH3:26])[CH3:25]
Reactant: Sc1ccccc1
Reactant: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(CSc2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
A solution of thiophenol, sodium salt and methanol is added to a solution of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(bromomethyl)nicotinic acid, methyl ester (14.08 g, 0.0298 mol) and methanol. The reaction mixture is stirred for 15 hours at room temperature, acidified with ammonium chloride (5 g, 0.0869 mol) and concentrated in vacuo to yield an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (3:1) to (1:1) as eluant to give the title compound as a yellow solid (8.32 g, 55%), mp 135°-138° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Br)=[O:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:7])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Br)c1cccc(CBr)c1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: O=C(c1cccc(CBr)c1)N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Into a 25 mL round bottom flask was added 3-bromomethyl-benzoyl bromide (1.39 g, 5 mmol) and benzene (5 mL). The flask was cooled to 0° C. with an ice bath and piperidine (852 mg, 2 eq) in benzene (3.3 mL) was added slowly. The reaction was stirred at 0° C. for three hours. The precipitate was removed by filtration on a Buchner funnel. The filtrate was concentrated to an oil which was purified by column chromatography with 20% ethyl acetate in hexanes to give the titled compound as a clear oil (578 mg, 41% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:22])([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][C:9]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccccc1
Yield: 72.4 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionate (1.55 g), which is the product of Reference example 8(b), 2-(2-bromoethoxy)tetrahydropyran (1.08 g) and potassium carbonate (2.14 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.60 g) as a syrup.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:47])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:47])[CH:39]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)n1ccc(I)cc1=O
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC(C)n1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=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)propyl)-1,3-oxazinan-2-one and 4-iodo-1-isopropylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.846 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.24 (s, 3H), 1.39 (d, 6H), 1.52 (d, 3H), 2.17-2.31 (m, 4H), 2.35-2.46 (m, 1H), 2.88 (m, 1H), 5.27 (m, 1H), 5.69 (m, 1H), 6.49 (d, 1H), 6.88 (s, 1H), 7.00 (d, 2H), 7.29-7.38 (m, 7H), 7.40 (d, 1H). Recrystallization from isopropyl acetate following a procedure analogous to that described for Example 37 in Recrystallization Method B afforded a crystalline solid with mp 134-139° C.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][CH2:24][S:23]4(=[O:28])=[O:27])=[CH:18][C:17]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:35]B(O)O>>[O:27]=[S:23]1(=[O:28])[CH2:24][CH2:25][CH2:26][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:33]=[CH:34][C:2]([CH3:35])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[O:15])=[C:17]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:18]=1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: CB(O)O
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)cc1
Yield: 50.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (138 mg) described in Preparation Example 22 and 4-(4-chlorobenzoyl)piperidine (97 mg) and by the reaction and treatment in the same manner as in Example 87, [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) was obtained. Using the obtained [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) and methylboronic acid (37 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (37 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14](Cl)[C:15]([F:18])([F:17])[F:16].Cl.[CH3:21][NH:22][CH3:23].C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([N:22]([CH3:23])[CH3:21])[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(Cl)=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
First, 0.34 g (1.0 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroacetoimidoyl chloride was dissolved in 10 ml of N,N-dimethylformamide, to which 0.08 g (1.0 mmol) of dimethylamine hydrochloride and 0.22 g (2.0 mmol) of triethylamine, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 0.28 g of N′-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoro-N,N-dimethylacetamidine (hereinafter referred to as present compound 52).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1)[CH3:29].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])([C:52](O)=[O:53])[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C>O1CCCC1.C(OCC)C>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([C:52](=[O:53])[NH:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=2)([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:48][CH2:47]1)=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2F)(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 65.7 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.650 g, 1.47 mmol) was added to a solution of 2-(4-ethyl-phenyl)-ethylamine (0.235 mL, 1.47 mmol), 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.330 g, 0.978 mmol) and triethylamine (0.409 mL, 2.93 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.301 g (65%) of 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester. LRMS m/z 469.1 (M+H)+.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:12]([C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([NH:29][C:24]1[C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:30]=[CH:31][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=2)=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:11]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 84.2 %

Procedure:
Using the procedure described in Example 102, Part A, 3-anisic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 610 mg (84%) of the title compound.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[O:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[O:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1coc(C=O)n1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)c1coc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added ethyl 2-formyloxazole-4-carboxylate (67.4 mg, 0.398 mmol) and sodium triacetoxyborohydride (97 mg, 0.460 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.0 mL) and sodium hydroxide (1 mL, 1.0 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to a TFA salt of the product. The TFA salt was treated with ACN (1 mL) and 1NHCl (0.5 mL) and concentrated. The residue was dried under vacuum to give 75 mg of product (HCl salt) as off-white solid. MS: (M+H)+=356.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.42 (q, 1H), 1.54-1.85 (m, 3H), 2.10-2.30 (m, 3H), 2.60 (ddd, J=10.36, 6.69, 3.66 Hz, 1H), 3.04 (dt, J=7.58, 4.04 Hz, 1H), 3.72-3.86 (m, 2H), 4.69 (s, 2H), 7.11-7.44 (m, 5H), 8.60-8.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([NH:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N>[CH2:27]([N:34]([C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:10][C:4]=12)[CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: OCCNCc1ccccc1
Solvent: CC#N
Product: OCCN(Cc1ccccc1)c1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.10 g, 0.25 mmol) and N-benzylethanolamine (0.3 g) were heated to 180° C. for 15 h. The reaction mixture was diluted with CH3CN and purified by HPLC-C18 to deliver the title product as the bis(trifluoroacetate) (44%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:16]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)Nc1ccc(I)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccn1)C(=O)Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of (S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-pyridin-2-yl-ethyl]-carbamic acid tert-butyl ester (1.2 g, 2.47 mmol) in dichloromethane (5 mL) at 0° C. was added trifluoroacetic acid (5 mL) and the mixture stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue suspended in ice cold water. The aqueous suspension was neutralized with saturated aqueous sodium carbonate solution to basic then extracted with dichloromethane (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% hexane up to 100% ethyl acetate in 40 minutes. Concentration of the product containing fractions gave (S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-pyridin-2-yl-propionamide as a yellow solid (806 mg, 85%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]([C:31]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:32]=1[CH:33]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:31]=3[O:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4 dimethoxylbenzaldehyde. MS (ESI) m/z 529.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[O:8]C(C(O)=O)=[CH:6][C:5]2=O.S(Cl)([Cl:19])=O.CN([CH:24]=[O:25])C>>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[O:8][C:24](=[O:25])[CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(=O)c2cc(Cl)c(Cl)cc2o1
Reactant: O=S(Cl)Cl
Product: O=c1cc(Cl)c2cc(Cl)c(Cl)cc2o1
Temperature: 70 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
6,7-Dichloro-4-oxo-4H-chromene-2-carboxylic acid (19.1 mmol) and thionyl chloride (20 mL) were carefully combined. DMF (0.2 mL) was added, and the dark, hetereogeneous solution was warmed to 70° C. After 16 h, the black homogeneous solution was cooled to ambient temperature and concentrated to a dark residue. The residue was diluted with CH2Cl2 (75 mL), washed with saturated aqueous NaHCO3 (2×75 mL), washed with brine (1×50 mL), dried (MgSO4), filtered, and concentrated to an orange residue that was passed through a plug of silica gel (1:1 hexane:EtOAc). The filtrate was concentrated to a beige solid (3.2 g) that was recrystallized from CH3CN to provide the desired solid (2.6 g, 55%) as off-white crystals. MS (APCI) m/z 273 [M+Na]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 7.06 (s, 1H) 7.99 (s, 1H) 8.06 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[Li+].[OH-].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (245 mg, 0.99 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.00 mL, 2.00 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (284 mg, 0.99 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave, after evaporation, 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 62 as a beige solid (46 mg, 9% yield).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6].O>C(O)C.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 5 h
Yield: 93.7 %

Procedure:
Z-Glu(Val-Gly-OBzl)-OBzl (6.20 g, 10.03 mmol) described above was suspended in ethanol (200 ml), 10% palladium on carbon (1.50 g) was added to the suspension, and a reduction reaction was performed under a hydrogen atmosphere at 55° C. for 5 hours. During the reaction, 100 ml in a total volume of water was gradually added. The catalyst was removed by filtration using a Kiriyama funnel, and the filtrate was concentrated under reduced pressure to a half volume. The reaction solution was further filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a small volume of water, and to the solution, ethanol was added to precipitate a crystal, and the crystal was collected by filtration and dried under reduced pressure to obtain γ-Glu-Val-Gly as a white powder (2.85 g, 9.40 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH2:20][CH2:21][CH2:22][OH:23])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1B from 4-[(2,2-dimethylpropyl)amino]-2-(trifluoromethyl)benzonitrile and [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.9 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.87 (dd, J=8.9, 2.5 Hz, 1H), 3.70 (app. bq, J=4.7 Hz, 2H), 3.62 (app. t, J=7.3 Hz, 2H), 3.27 (s, 2H), 1.87-1.75 (m, 2H), 1.47 (bt, J=4.2 Hz, 1H), 0.99 (s, 9H).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[CH3:13][N:14]1[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=O)[O:16]C1=O.Cl>O.C(O)C>[OH:16][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:14]([CH3:13])[C:4](=[O:6])[C:3]=1[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2cccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.345 g. (0.15 g. atom) of sodium in 30 ml. of ethanol was added 4.8 g. of diethyl malonate. The mixture was stirred at room temperature for 5 minutes and then was evaporated in a rotary evaporator. The residue was dissolved in 30 ml. of N,N-dimethylformamide and 2.67 g. (0.015 mole) of 1-methyl-1H-4H-pyrido[2,3-d][1,3]-oxazine-2,4-dione was added. The mixture was heated under reflux for 10 minutes and the thick mixture was dissolved in 100 ml. of water. The solution was acidified with conc. hydrochloric acid and the precipitate which formed was collected, air dried, and a small amount of this 1.7 g. was recrystallized from ethanol to give the analytical sample of 4-hydroxy-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p. 158°-160° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH:62]=[CH:61][N:60]=[C:59]1[C:63](O)=[O:64]>CN1C(=O)CCC1>[CH3:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:63]([C:59]4[N:58]([CH3:57])[CH:62]=[CH:61][N:60]=4)=[O:64])[CH2:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([CH3:23])[C:15]1=[O:22]
Reactant: Cn1ccnc1C(=O)O
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)NC1CC=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round bottom flask were added 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) (0.0010 g, 0.028 mmol), DIPEA (0.050 mL, 0.286 mmol), HATU (0.0013 g, 0.034 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (0.00467 g, 0.037 mmol), and NMP (1 mL). The reaction was stirred at room temperature overnight (˜14 hours), the reaction mixtures were then filtered & purified by reverse-phase chromatography (5-95% 0.1% TFA in H2O:acetonitrile) to give N-{4-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}-1-methyl-1H-imidazole-2-carboxamide (17-3). HRMS m/z (M+H): calculated=423.2503; observed=423.2507.