Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:14][NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:14][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CNc1cnccc1-c1ccccc1C
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a solution of 4-(trifluoromethyl)benzoic acid (115 mg, 605 μmol, CAS RN 328-90-5) in CH2Cl2 (2 mL) were added N-methyl-4-o-tolylpyridin-3-amine (0.1 g, 504 μmol, example 1, intermediate a), 2-bromo-1-ethylpyridinium tetrafluoroborate (166 mg, 605 μmol, CAS RN 878-23-9) and DIPEA (130 mg, 176 μL, 1.01 mmol). The reaction mixture was stirred at room temperature for 66 h. The red solution was poured on 10% aqueous citric acid and dichloromethane and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with 10% aqueous citric acid solution and brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with EtOAc (isocratic). The compound-containing fractions were evaporated and the residue was dissolved in dichloromethane and the solution washed twice with 2M aqueous Na2CO3 solution, twice with 1M aqueous HCl and once with brine, dried over MgSO4, filtered and evaporated. Brown solid (16%). MS (ESI): m/z=371.14 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C)[C:7](=[O:15])[CH2:6][CH2:5]2.C([O:18][C:19]([NH:21][NH2:22])=[S:20])C.[C:23](#N)[CH3:24]>>[O:20]=[C:19]1[NH:21][N:22]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:15])[CH2:6][CH2:5]3)[CH2:23][S:18]1
Reactant: CC(=O)N1C(=O)CCc2cc(Cl)ccc21
Reactant: CC#N
Reactant: CCOC(=S)NN
Product: O=C1CCc2cc(C3=NNC(=O)SC3)ccc2N1
Reaction time: 2 h

Procedure:
To a solution of acetonitrile (100 ml) were added 6-chloro-acetyl-3,4-dihydro-2(1H)-quinolinone (6.7 g) and ethoxythiocarbonylhydrazine (5.4 g) and the mixture was stirred for 2 hours, cooled and then filtered off. The filtrate was recrystallized from dimethylformamide (30 ml) and water (10 ml) to obtain pale yellow 6-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,4-dihydro-2(1H)-quinolinone (5.2 g), melting at 271°-272° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].COCCl.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4-hydroxyphenyl)ethanol (1.4 g) in tetrahydrofuran (30 ml) was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the stirred reaction mixture was added chloromethyl methyl ether (770 μl) under ice-cooling, and the resulting mixture was stirred for 16 hours at room temperature. Additionally, to the stirred reaction mixture was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling. After the mixture was stirred for 1 hour at room temperature, benzyl bromide (1.2 ml) was added under ice-cooling and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 ml), trifluoroacetic acid (20 ml) was added to the solution under ice-cooling with stirring, and the mixture was stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution (20 ml) and water (20 ml) were added to the residue, and the resulting mixture was vigorously shaken. The aqueous layer was separated, washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent:hexane/diethyl ether=2/1) gave 4-(2-benzyloxyethyl)phenol (440 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].N1CCC[CH2:14]1.CC(O)=O.[OH-].[Na+]>O1CCOCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:14][NH:9]2
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100° C. for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50% aq. NaOH and extracted with EtOAc (2×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with an EtOAc/petroleum ether gradient (5 to 30% EtOAc) to afford 1.16 g (27%) of 4-bromo-6-fluoro-1H-indole (224)—as brown solid: MS (ESI) m/z=213.9 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])=[CH:4][C:3]=1[N+:18]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1ccc(F)c(N)c1

Procedure:
A mixture of N-[(4-fluoro-3-nitrophenyl)carbamoyl]glycine, ethyl ester (8 g, 0.029 mol) and 5% platinum on activated carbon (0.5 g) in ethyl acetate is hydrogenated at 50 psi until hydrogen uptake is complete. The reaction mixture is then filtered and cooled in an ice-bath until a solid forms. The solid is collected by filtration and air-dried to give the title product as a white solid.(4.5 g, mp 152°-153° C.).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([O:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])(=[O:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:9]([O:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])([CH3:22])[CH3:21])(=[O:11])[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)OCCC(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(=O)OCCC(C)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
11.0 Parts of resorcinol, 10.0 parts of citronellyl acetate and 0.5 parts of p-toluene sulphonic acid are heated at 115° C. for 45 hours. The reaction mixture is then taken up in ether, washed with sodium bicarbonate solution, water, and evaporated. The residual oil is distilled and yields 3.9 parts of 7-(2,4-dihydroxyphenyl)-3,7-dimethyloct-1-yl acetate b.p. (0.2) 215° C. with the following percentage composition by weight:
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 49H in water (3 mL) was treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.70 (s, 9H) 0.81 (m, 1H) 1.38 (s, 3H) 1.71 (m, 1H) 2.16 (m, 1H) 2.90 (s, 3H) 7.28 (m, 3H) 7.44 (m, 3H) 8.05 (d, J=7.35 Hz, 1H) 9.87 (s, 1H) 15.44 (s, 1H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:14]1([C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (758 mg, 4.18 mmol) was dissolved in DMF (25 mL) and morpholine (603 uL, 5.23 mmol), Et3N (2.45 mL, 16.7 mmol) and HBTU (1.67 g, 4.39 mmol) were added. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat aq Na2CO3 (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (914 mg, 87.3%) as a yellow oil. LCMS (ES+): 251.2 [MH]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][S:10][C:9]1=[N:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>>[NH2:15][C:14]1[NH:18][N:17]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][SH:10])[N:13]=1
Reactant: N#CN=C1SCCN1Cc1ccccc1
Reactant: NN
Solvent: O
Product: Nc1nc(N(CCS)Cc2ccccc2)n[nH]1

Procedure:
A mixture of 1.84 g of 3-benzyl-2-cyanoiminothiazolidine and 10 ml of hydrazine monohydrate was heated at reflux under an algon atmosphere for an hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 2 g of 5-amino-3-[N-(2-mercaptoethyl)benzylamino]-1,2,4-triazole (Compound 1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH2:30]=O>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH3:30])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: C=O
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and formaldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2; Found: 401.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[S:34](O)(=O)=O>C(=O)(O)[O-].[Na+]>[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[S:34][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: Oc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A mixture of 3.7 g 2-aminophenol, 4.2 g 4-hydroxybenzoic acid, 4.5 g phosphorus pentoxide and 45 g methanesulfonic acid was stirred for one hour at room temperature and then heated at 90° C. for 10 hours. The reaction mixture was poured slowly into 750 ml 5% sodium bicarbonate solution. The solid which precipitated was collected and dried to give 7.0g 2-(4-hydroxyphenyl)-benzothiazole.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:38])([CH3:37])[C:4]([N:6]([C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[CH2:27][C@@:17]3([C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:16][C:13]2=[N:14][CH:15]=1)=[O:5].[Na+].[I-:40]>CC(C)=O>[C@H:28]1([N:6]([CH2:7]/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[CH2:27][C@@:17]4([C:25]5[C:20](=[N:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])[CH2:16][C:13]3=[N:14][CH:15]=2)[C:4](=[O:5])[C:3]([CH3:37])([CH3:38])[CH2:2][I:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(CCl)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(CI)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2-dimethyl-N-{(2E)-3-[(6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl]prop-2-en-1-yl}propanamide (120. mg, 0.228 mmol) in acetone (2.3 mL) was added NaI (683 mg, 4.55 mmol). This mixture was heated to 120° C. in a microwave reactor for 30 minutes. After cooling, the bulk of the acetone was removed in vacuo and the residue was partitioned between DCM and water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-8% MeOH (containing 10% conc. NH4OH) in DCM to provide the title compound. MS: m/z=619 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:41]([O:43][C:44]1[C:45](=O)[C:46](=[O:51])[C:47]=1[O:48]CC)[CH3:42]>C(Cl)Cl.CCOC(C)=O>[CH2:41]([O:43][C:44]1[C:47](=[O:48])[C:46](=[O:51])[C:45]=1[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:42]
Reactant: COC(=O)[C@H](COc1ccc(-c2cccc(N)c2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1c(Nc2cccc(-c3ccc(OC[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)OC)cc3)c2)c(=O)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The compound of Example 3 (1.50 g, 2.8 mmol, 1 equiv) was dissolved in 3,4-diethoxy-3 cyclobutene-1,2-dione (2.1 mL, 14.2 mmol, 5 equiv). The reaction mixture was stirred at 60-70° C. for 1 h. It was then allowed to cool to rt and diluted with CH2Cl2/EtOAc 9:1 (12 mL). The solution was filtered over a pad of silica gel and eluted with CH2Cl2/EtOAc 9:1. Unreacted 3,4-diethoxy-3-cyclobutene-1,2-dion eluted first followed by the title compound. Yield 0.68 g, 36.7%. 1H NMR (CDCl3, 7.72-7.51 (m, 8H); 7.48-7.32 (m, 3H); 7.29-7.03 (m, 10H); 6.94 (d, 2H); 4.94 (q, 2H); 4.29 (dd, 1H); 4.14 (dd, 1H); 3.85-3.69 (m, 1H); 3.23 (s, 3H); 2.90 (d, 1H); 1.55 (t, 3H). MS (ESI) 675 (M+Na), 653 (M+H), 243 (CPh3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19]Cl)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][O:18][CH3:19]
Reactant: CCOCCl
Reactant: Oc1ccc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification. Step 2: A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification. Step 3: A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc(II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].Cl.[NH2:33][CH2:34][CH2:35][N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38].C[O-].[Na+]>CCO>[CH3:40][S:37]([N:36]([CH3:41])[CH2:35][CH2:34][NH:33][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4])(=[O:39])=[O:38]
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN(CCN)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 67.8 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.061 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (57 mg, 0.30 mmol), and NaOMe (16 mg, 0.30 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 22 mg of the title compound as a light yellow solid. MS: (+) m/z 532.11 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)OCC)ccc1OC
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid ethyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:16][CH2:17]1)=[O:30])[C:7]([N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1)=[O:9]
Reactant: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=C(C[C@H](Cc1cc(Cl)c(O)c(C(F)(F)F)c1)C(=O)N1CCC(N2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example (1 g) from 70 mg (0.126 mmol) (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-butanoic acid and 22 mg (0.130 mmol) 4-piperidin-4-yl-morpholine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:39]([NH:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=3)=[O:40])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: COc1cccc(N=C=O)c1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3cccc(OC)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 25 mg (0.17 mmol, 1.1 eq.) of 3-methoxyphenyl isocyanate were reacted according to General Method 4. Yield: 46 mg (67% of theory)