Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:18])[CH:10]=2)=[C:5](S(C)(=O)=O)[C:4]([CH3:23])=[N:3]1.CN1CCCC1=[O:30].[OH-].[Na+]>O>[OH:30][C:5]1[C:4]([CH3:23])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1
Reactant: Cc1nn(C)c(=O)c(-c2cn(C)c3ccccc23)c1S(C)(=O)=O
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(=O)c(-c2cn(C)c3ccccc23)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 20 ml volume two-necked flask, 2,6-dimethyl-4-(1-methyl-1H-indol-3-yl)-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-203)-(13)-28) (0.30 g), N-methyl-2-pyrrolidone (1.17 ml), and a aqueous solution of sodium hydroxide (0.14 g) in water (0.6 ml) were added under a nitrogen atmosphere, and stirred at 70° C. for 2 hours. The reaction mixture was added to iced water, and washed with ethyl acetate. The pH of the resulting aqueous layer was adjusted to 5 with cold dilute hydrochloric acid under ice-cooling. The precipitated solids were collected by filtration, washed with water, and dried to give 0.18 g of 5-hydroxy-2,6-dimethyl-4-(1-methyl-1H-indol-3-yl)-2,3-dihydro-3-pyridazinone ((1-201)-(12)-10).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[NH2:13][C:14]1[C:22]([I:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([I:23])[C:14]([NH2:13])=[CH:15][C:16]=2[O:24][CH3:25])[CH2:7]1
Reactant: COc1cc(N)c(I)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(N)c(I)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-amino-5-iodo-2-methoxybenzoic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (0.2 ml.) was added during 10 minutes to a stirred solution of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.79 g.) in concentrated sulphuric acid (1.5 ml.) maintained at a temperature of 0°-5° C. The reaction mixture was then stirred at 0°-5° C. for 1 hour and finally at 5°-20° C. for a further 1 hour. The solution was then poured onto crushed ice (300 g.) and the mixture which formed was extracted with ethyl acetate. The combined extracts were washed with water (3×150 ml.) then with brine (100 ml.) and dried (MgSO4). The extracts were evaporated and the residual oil was redissolved in ethyl acetate (20 ml.). The solution was evaporated on to chromatographic silica gel and the solid residue added to the top of a column of the same silica gel made up in toluene. The column was eluted with increasing concentrations of ethyl acetate in toluene (up to 1:1 v/v). The fractions containing the major component [TLC:Rf~0.6 on SiO2 :eluant 1:1 v/v EtOAc/toluene] were combined and evaporated. The residue was recrystallised from a mixture of toluene, ethyl acetate and petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-nitro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (Prep. 35) (0.46 g.), m.p. 249°-251° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]#[C:22][C:23](OC)=[O:24])=[O:20]>CO>[CH3:17][O:18][C:19](=[O:20])[CH:21]=[C:22]1[S:9][C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:23]1=[O:24]
Reactant: COC(=O)C#CC(=O)OC
Reactant: S=C(NC1CCCCC1)NC1CCCCC1
Solvent: CO
Product: COC(=O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of N,N'-dicyclohexylthiourea (10.0 g, 42 mmoles) and dimethylacetylenedicarboxylate (7.8 g, 55 mmoles) in methanol (100 mls) is stirred at room temperature for 16 hours, then warmed on a steambath for 45 minutes and cooled. The precipitate is filtered off, rinsed with cold methanol and dried. This gave the product as white crystals, (11.3 g), mp 97°-98° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.S1(CCCC1)(=O)=O.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a mixture of 308 mg (purity: 99.0%; 1.85 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.47 mmol) of 2-cyclopropyl-6-methylphenol were added sulfolane (2.76 g) and 332 mg (5.63 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 181 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 36%) and 7.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 1.4%) were obtained.
Reaction SMILES: COC1C=CC([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]2[C:22]3[C:21](=[O:23])[NH:20][C:19]([NH2:24])=[N:18][C:17]=3[N:16]=[CH:15]2)=CC=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19]([NH2:24])=[N:18][C:17]=2[N:16]=[CH:15]1
Reactant: COc1ccc(OCCOCn2cnc3nc(N)[nH]c(=O)c32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: Nc1nc2ncn(COCCO)c2c(=O)[nH]1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 8 (1.36 g, 4.10 mmol) in a mixture of CH3CN (30 mL) and water (10 mL) was added CAN (2.25 g, 4.10 mmol) at 0° C. The stirred reaction mixture was allowed to warm-up to 25° C. within 1.0 h. Water (30 mL) was added to afford a solid. Filtration and crystallization of the solid from EtOH/water (4:1) gave 9 (0.65 g, 2.88 mmol) in 70% yield: mp>280° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.08; UV (EtOH) λmax 289 (ε 16,000); 1H NMR (DMSO-d6) δ 3.61-3.82 (m, 4H, O(CH2)2O), 4.85 (br s, 1H, OH), 5.81 (s, 2 H, H2C1′), 5.96 (br s, 2 H, NH2), 6.61 (s, 1 H, NH), 8.67 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 60.91 (CH2OH), 70.01 (OCH2) 75.25 (C1′), 107.16 (C5), 143.92 (C8), 153.20 (C4), 154.40 (C2), 159.30 (C6); MS m/z 225 (M+). Anal (C8H11N5O3) C, H, N; calcd (%): 42.66, 4.92, 31.10; found (%): 42.75, 4.84, 31.21.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH2:26].Cl>C(OCC)C.O1CCOCC1>[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(Br)c(N)c(Br)c1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(Br)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(Br)c1
Temperature: 170 °C
Yield: 16 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethyl ether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heated under Ar until all diethyl ether had evaporated. The tube was sealed and heated at 170° C. for 2.5 days. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 99:0.9:0.1). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile, filtered off and dried, yielding 0.22 g (15.9%) of 4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 61).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[N:30][CH:31]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:31]=[N:30][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[CH:28][CH:27]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cn2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)cn2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (16% yield). MP 210-215° C. 1H NMR (400 MHz, (CDCl3, δ, ppm): 8.79 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.14 (d, J=7.3 Hz, 2H), 7.90 (d, 1H), 7.80 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.96 (d, 1H), 6.88 (s, 1H), 3.21 (bm, 4H), 3.13 (s, 3H), 2.66 (bm, 4H), 1.57 (s, 3H). MS=532.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH2:29][C:30]([OH:32])=[O:31])[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:12])=[O:11])[CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH2:29][C:30]([OH:32])=[O:31])[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:12])=[O:11])[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: C#Cc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1

Procedure:
104 mg [(3-chloro-5-ethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetic acid are dissolved in 5 ml of ethyl acetate. 30 mg of platinum dioxide are added and the mixture is hydrogenated for 5.5 hours at 3 bar hydrogen pressure. Then the catalyst is removed by suction filtering, the solvent is eliminated in vacuo and the residue is purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.[C:23](I)([F:26])([F:25])[F:24].OO>CS(C)=O>[CH3:1][N:2]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:5]2[CH2:4][CH2:3]1
Reactant: FC(F)(F)I
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: OO
Solvent: CS(C)=O
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Yield: 63.9 %

Procedure:
To tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (10.0 g, 32.7 mmol) in DMSO (164 mL) was added ferrous sulfate heptahydrate (9.8 mL of 1.0 M, 9.8 mmol) followed by CF3I (6.41 g, 32.7 mmol) by slow bubbling through the solution and taking the weight difference of the canister. The mixture was cooled with a ice-water bath before H2O2 (3.71 mL of 30% w/v, 32.7 mmol) dropwise over 15 min keeping the internal temperature<20° C. The mixture was poured onto 300 mL of ice water and was extracted with EtOAc (2×400 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified column chromatography eluting with 0-10% methanol in dichloromethane with 2% iPr2NEt to give tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (7.8 g, 64%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=[O:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=O

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (70 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone for 13 minutes at -78° C. to give 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-formylmethyloxiranyl)-1-oxaspiro-[2,5]octane in the reacting mixture. After babbling of nitrogen, methyl sulfide (0.2 ml) was added to the mixture at the same temperature. The mixture was stirred at -78° C. for 15 minutes and allowed to warm to 0° C. followed by the addition of carboethoxymethylene-triphenylphosphorane (150 mg). The mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1) to yield 6-cyclohexylcarbamoyloxy-4-[3-(3-ethoxycarbonyl-2-propenyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (53 mg) as an oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2ccccc2)c1
Yield: 65 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 305 mg of 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=76° C.). Yield=65% over the two steps.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[O:3]1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]2=[O:12])[CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
A solution of 50 g (0.26 mol) of 2,2-dimethyl-6-hydroxychroman-4-one (Example 1a) in 500 ml of DMF was added dropwise to a suspension of 9.0 g (0.3 mol) of 80 percent sodium hydride in 500 ml of DMF. The mixture was stirred at RT for 90 min, 49 g (0.265 mol) of iodobutane were added and the mixture was stirred at RT for a further 90 min. The reaction mixture was then concentrated under reduced pressure and the residue was admixed with water and extracted repeatedly with EA. The organic phases were washed with 5 M aqueous sodium hydroxide solution, stirred with activated carbon and magnesium sulfate, filtered and concentrated. This procedure gave 57.6 g of 6-butoxy-2,2-dimethylchroman-4-one.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:29]I.O>C1COCC1>[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:29])[C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 159.6 %

Procedure:
To a solution of 3.00 g (8.19 mmol) of Boc-Orn (Z)-OH in 82 ml of THF were added 1.31 g (32.8 mmol) of 60% sodium hydride and 4.08 ml (65.5 mmol) of methyl iodide with ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was combined with water with ice cooling, and washed with hexane. The aqueous layer was combined with 10% aqueous citric acid solution, extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 3.22 g (100%) of Boc-N-Me-Orn (Me) (Z)-OH.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[O:39])=[CH:36][N:35]=[CH:34]1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.28 mL, 0.7 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.303 g, 0.707 mmol, Intermediate 10) in dry THF (7 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.144 g, 0.769 mmol, Intermediate 33: step b) in dry THF (0.5 mL) was added dropwise. The reaction was stirred for 5 minutes, switched to an ice bath for 10 minutes, then removed from the cold bath and allowed to warm to ambient temperature. The reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness. Impurities remained in the sample, therefore the product was taken forward to the chiral separation step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+].ClCCl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19](=[NH:20])[O:22][CH3:21])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: N#Cc1cccc(-c2cnc(-c3cncc(F)c3)s2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=N)c1cccc(-c2cnc(-c3cncc(F)c3)s2)n1

Procedure:
6-[2-(5-Fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carbonitrile (0.33 g, 1.17 mmol) and sodium methoxide (0.13 g, 0.23 mmol) were stirred in methanol (10 ml) and dichloromethane (10 ml) at room temperature for 3 d. The precipitated solid was filtered off and the solvent of the filtrate was removed under reduced pressure. The residue was dissolved in dichloromethane and filtered through Celite. The solvent of the filtrate was removed under reduced pressure. This gave 0.32 g (83% of theory) of methyl 6-[2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carboximidoate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]2[S:6][C:2]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)=[CH:3][N:4]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Nc2ncc(Br)s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Temperature: 120 °C

Procedure:
A mixture of (5-bromo-thiazol-2-yl)-(4-methoxy-phenyl)-amine (203 mg, 0.710 mmol), 3-thiophene-boronic acid (268 mg, 2.10 mmol, 6.0 equiv), Pd(PPh3)4 (12 mg, 0.0105 mmol, 0.03 equiv), Na2CO3 (326 mg, 3.08 mmol, 8.8 equiv), and water (305 μL, 16.7 mmol, 24 equiv) in toluene (10 mL) is heated in a sealed tube to 120° C. for 1 h, under an argon atmosphere. The resulting suspension is allowed to cool to RT and filtered through a pad of celite, washing the filter cake with CH2Cl2 and water. The layers are separated. The organic phase is dried (Na2SO4), filtered and concentrated. Purification by MPLC (CH3CN/H2O/TFA) affords the title compound as a light beige solid: ES-MS: 289.0 [M+H]+; single peak at tR=7.43 min (System 1); Rf=0.56 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:33])[C:31]#[CH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:33][CH2:30][C:31]#[CH:32])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: C#CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with propargylamine (0.013 mL, 0.19 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(2-propynylaminomethyl)indol-2-yl]isoindolinone.