Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:24])=[CH:4][CH2:5][CH2:6][C:7]([CH3:23])=[CH:8][CH2:9][CH2:10][C:11]([CH3:22])=[CH:12][CH:13]=[C:14]([CH:19]([CH3:21])[CH3:20])[CH:15]([OH:18])[C:16]#[N:17].[CH:25]([O:27][CH2:28][CH3:29])=[CH2:26].C(=O)([O-])O.[Na+].CCCCCC.CCOCC>ClCCl>[Cl:1][CH2:2][C:3]([CH3:24])=[CH:4][CH2:5][CH2:6][C:7]([CH3:23])=[CH:8][CH2:9][CH2:10][C:11]([CH3:22])=[CH:12][CH:13]=[C:14]([CH:19]([CH3:20])[CH3:21])[CH:15]([O:18][CH:25]([O:27][CH2:28][CH3:29])[CH3:26])[C:16]#[N:17]
Reactant: C=COCC
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(C(C)C)C(O)C#N)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(C)OC(C#N)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
To a solution of 15-chloro-2-hydroxy-3-(1-methylethyl)-6,10,14-trimethyl-3,5,9,13 pentadecatetraenenitrile (204 mg, 0.56 mmol) prepared in Reference Example 6 and ethyl vinyl ether (100 μl, 0.96 mmol) in dichloromethane (5 ml) is added a very small amount of paratoluenesulfonic acid while stirring under nitrogen atmosphere on an ice-water bath. After 10 minutes, to the mixture are added a saturated aqueous sodium hydrogencarbonate solution (15 ml) and n-hexane/ether (1:1) solution (20 ml) and the organic layer is separated. The aqueous layer is then extracted with n-hexane/ether (1:1) solution (20 ml) for several times. The organic layers are combined and dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure. The resulting residue is purified by silca gel column chromatography (n-hexane/ethyl acetate =20:1) to give 15-chloro-2-(1-ethoxyethoxy)3-(1-methylethyl)-6,10,14-trimethyl-3,5,9,13-pentadecatetraenenitrile (207 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([NH2:12])[CH3:11]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:12][CH:10]([CH3:11])[CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)Nc1nccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
2,3-dichloropyrazine (10 g, 67.1 mmol), propan-2-amine (11.90 g, 201 mmol), and 50 mL of THF were mixed in a three-neck flask and stirred at room temperature overnight. The reaction was brought to reflux overnight. The reaction was cooled and the solvent was evaporated. The residue was dissolved in dichloromethane and the salt was filtered. The solvent was then evaporated and the residue was purified by column using dichloromethane as solvent to give 3-chloro-N-isopropylpyrazin-2-amine (6.2 g, 53.8%).
Reaction SMILES: FC1C=C2C(C(C3CCN(CCN)CC3)=[N:7]N2)=CC=1.F[C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[C:25]1(=[O:26])[NH:7][C:28](=[O:27])[C:23]2=[CH:22][CH:21]=[CH:31][CH:30]=[C:24]12
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 80 °C

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed at 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55° C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186-188° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29].CS(C)=O.CO>COCCOC.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>[CH3:1][N:2]1[CH:6]=[C:5]([C:23]2[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:27]([CH:37]=2)[C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])[CH:4]=[N:3]1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CO
Solvent: COCCOC
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 140 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.9 mg, 0.273 mmol), 1M Na2CO3 (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 6 mol %) were added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 6; 100 mg, 0.26 mmol) in 1,2-dimethoxyethane (3 ml). The solution was heated at 140° C. in microwave for 35 minutes. The solvent was removed in vacuo to give a residue. Trituration with 1:1 dimethyl sulfoxide/methanol (0.6 ml) gave the product as a solid which was washed with methanol (2 ml) and ethyl acetate (5 ml) to yield the title compound as a grey solid. 45 mg.
Reaction SMILES: OCC[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[C:11]([O-:15])(=[O:14])[CH:12]=[CH2:13].[Cl-].N1C=CC=[CH:19][CH:18]=1>>[C:11]([O:15][CH2:18][CH2:19][S:10][C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)[O-]
Reactant: OCCc1ccccc1S
Reactant: c1ccncc1
Agent: [Cl-]
Product: C=CC(=O)OCCSc1ccccc1
Yield: 80 %

Procedure:
60 g of hydroxyethyl benzene thiol and 44.7 g of chloride acrylate were reacted in 244 g of pyridine at 25° C. for 4 hours and then formed by distillation into 2-(phenylthio)ethyl acrylate with 80% yield. A synthetic monomer 6 was obtained with 82% yield in the same manner as in Synthesis Example 1 except that 2-(phenylthio)ethyl acrylate was used in place of phenoxyethyl acrylate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@@H:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[C@@H:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (3 mL) was added oxalyl chloride (0.040 mL, 0.46 mmol) and DMF (1 drop). After 20 min at room temperature, the mixture was concentrated in vacuo and the residue was added to another flask containing 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in CH2Cl2 (3 mL). The resulting mixture was stirred at room temperature for 20 min, quenched with saturated aqueous NaHCO3 solution (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-8% MeOH/EtOAc) to afford the titled compound (0.030 g, 44%, TFA salt) as a white solid. 1H NMR (TFA salt) (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.43 (s, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.20 (dd, J=8.8, 8.4 Hz, 2H), 5.61 (q, J=7.2 Hz, 1H), 3.89 (m, 2H), 2.84 (dd, J=6.2, 6.2 Hz, 2H), 2.65 (s, 3H), 2.15 (m, 2H), 1.84 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O [M+H]+ (free form) 422.1, found 422.1; The titled compounds were analyzed by chiral normal phase chromatography (RegisPack, 25 cm×4.6 mm, 5 micron, cat#793104, 0.1% DEA/IPA, 0.7 mL/min). The (S)-enantiomer (major) had a retention time of 7.2 min and the (R)-enantiomer (minor) had a retention time of 6.2 min (isolated in 19:1 er).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1CCC(=O)O
Yield: 56.9 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (220 mg), 147 mg 5-chloro-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 172 mg of the title compound (50%) as a brown solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:22]([N:14]([CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: ClCc1ccccc1
Reactant: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CN(Cc2ccccc2)c2ccc(Nc3ccccc3)cc2)cc1

Procedure:
A well-stirred mixture of N-phenyl-p-phenylenediamine (22.1 g, 0.12 mol) and triethylamine (26.7 g, 0.26 mol) in toluene (300 ml) is treated with benzyl chloride (30.4 g, 0.24 mol). The resulting mixture is warmed to 70°-75° C. for five hours, then cooled and washed with water. The organic fraction is concentrated to an oil that is chromatographed (silica gel; heptane:ethyl acetate) to give the title compound in a yield of 15 g (34%) as a yellow solid melting at 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C[S:22]([C:25]1C=CC(CNC)=C[CH:26]=1)(=[O:24])=[O:23].C(S(Cl)(=O)=O)C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CNCc1ccc(S(C)(=O)=O)cc1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Product: Cl

Procedure:
The process is analogous to the method described in example 82, starting from the compound of example 17, intermediate 1, and ethanesulfonyl chloride.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.CC(C)=O.Cl>[CH2:27]([O:26][CH2:25][C:23]1[CH:24]=[N:20][NH:21][CH:22]=1)[CH3:28]
Reactant: CCOCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CCOCc1cn[nH]c1
Temperature: 80 °C
Yield: 44 %

Procedure:
1-trityl-4-ethoxymethylpyrazole (1.800 g, 4.88 mmol) was dissolved in a mixture of ethanol/acetone (15 ml/5 ml) and 30 mL of 2N HCl was added to the resulting solution. The mixture was heated at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was filtered and washed with dichloromethane. The aqueous layer was basified with 2N NaOH and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and the solvent was evaporated under vacuum yielding compound 4-ethoxymethylpyrazole as a white oil. Yield: 44% (270 mg, 2.14 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11](O)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[CH3:62][CH2:61][C@@H:59]([C@H:53]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:52]([NH:51][C@H:43]([C@@H:42]([OH:64])[CH2:41][N:40]([NH:65][C:11]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:12])[CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]2[S:28][CH:29]=[N:30][CH:31]=2)=[CH:38][CH:37]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:63])[CH3:60]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 213-216° C.; HPLC20-100 : tRet =14.7; FAB MS (M+H)+ =711.
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([OH:46])=[C:33]([C:35]2(O)[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:44])[CH:34]=1>>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([OH:46])=[C:33]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:44])[CH:34]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc(Br)ccc1O
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1Nc2ccccc2C1c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one, the title compound was obtained (98%) as a white powder: MS (ES+) m/z 306.2 (M+1), 304.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:18]=1)[C:15](O)=O.[OH-].[Na+]>O>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:15]1[C:14]1[CH:18]=[C:10]([NH2:9])[CH:11]=[N:12][CH:13]=1
Reactant: Nc1cncc(C(=O)O)c1
Reactant: Nc1ncccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cncc(-c2nc3ncccc3o2)c1
Temperature: 200 °C
Reaction time: 6 h

Procedure:
In a typical run, 790 mg of 2-amino-3-hydroxypyridine (7.24 mmol) and 1.00 g of 5-aminonicotinic acid (7.24 mmol) were mixed with 10 mL of PPA and stirred at 200° C. for 6 hours. The reaction mixture was cooled to about 100° C. and carefully poured into 100 mL of water. The pH was brought to 6 with solid NaOH and the solids were collected by filtration. After drying under high vacuum, a total of 180 mg of 5-oxazolo[4,5-b]pyridin-2-yl-pyridin-3-ylamine.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[CH:25]=[N:24][C:23]([NH2:31])=[CH:22]2.C(OCC)(=O)C>ClCCl.C(OCC)(=O)C.CCCCCC>[N:31]([C:23]1[N:24]=[CH:25][C:26]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:18][CH3:17])=[C:28]([O:29][CH3:30])[CH:27]=2)=[C:1]=[S:2]
Reactant: COc1cc2cnc(N)cc2cc1OC
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc2cnc(N=C=S)cc2cc1OC

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (124.6 mg, 0.536 mmol) in dichloromethane (3 mL) was added a suspension of 6,7-dimethoxyisoquinolin-3-amine (105 mg, 0.514 mmol) in dichloromethane (5 mL). The reaction mixture was applied directly to a Biotage column in 15-25% ethyl acetate/hexane followed by 100% ethyl acetate to give 3-isothiocyanato-6,7-dimethoxyisoquinoline as a white solid. Yield 69.4 mg (55%) NMR 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.81 (1H, s), 7.31 (1H, s), 7.16 (1H, s), 6.98 (1H, s), 3.99 (6H, s)
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Mg]I>C(OCC)C.C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[C:7]1=[O:8])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Clc1ccccc1[Mg]I
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (4 g, 9.09 mmol) in a mixture of diethyl ether (60 mL) and toluene (20 mL) was added dropwise a freshly prepared 0.67 N 2-chlorophenylmagnesium iodide in ether (15 mL, 10.1 mmol) over 20 min at room temperature. The mixture was stirred for 20 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were washed with sat. aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 100:1 to 50:1 chloroform/methanol to give the title compound (2.81 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:43][CH2:42]2)[S:9]1(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccccc3Cl)S2(=O)=O)CC1
Yield: 60.8 %

Procedure:
In an analogous manner as general procedure II, step 1, a solution of 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.23 g, 0.8 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.32 g, 1.2 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.37 g, 1.6 mmol) were added followed by diisopropylazodicarboxylate (0.23 mL, 1.2 mmol) to provide tert-butyl 4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.24 g, 61%) as a white foam:
Reaction SMILES: Cl[C:2]1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[CH:47]=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[CH3:68][CH:69]([CH3:73])[C:70](=[S:72])[NH2:71]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:72][C:70]([C:69]([CH3:2])([CH3:73])[CH3:68])=[N:71][C:44]=2[C:46]2[CH:47]=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)C(N)=S
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 44.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-4-fluorophenyl}carbamate (20 g, 57.3 mmol), NBS (10.2 g, 57.3 mmol) and 2-methylpropanethioamide (7.4 g, 63 mmol) the title compound of Step C was obtained (11 g, 44.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90-9.98 (br, 1H), 8.61 (d, J=5.3 Hz, 1H), 7.65-7.72 (m, 1H), 7.49-7.54 (m, 1H), 7.21-7.30 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 5.90-6.05 (m, 1H), 5.20-5.40 (m, 2H), 4.58-4.63 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[C:29]([CH2:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=1>>[O:36]=[C:34]([CH3:35])[CH2:33][C:29]1[CH:28]=[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: CC(=O)Cc1cccc(Br)c1
Product: CC(=O)Cc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide and 1-(3-bromophenyl)-2-propanone in a similar manner to Example 1.
Reaction SMILES: [CH3:1]I.[N+:3]([CH:6]([CH2:8][CH:9]([CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:7])([O-:5])=[O:4].[OH-].[Na+]>CC(C)=O>[N+:3]([CH:6]([CH2:8][CH:9]([CH2:18][C:19]([N:21]([CH3:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:7])([O-:5])=[O:4]
Reactant: CI
Reactant: CCCCCCCCC(CC(=O)Nc1ccccc1)CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCCCC(CC(=O)N(C)c1ccccc1)CC(C)[N+](=O)[O-]
Reaction time: 0.13 h
Yield: 97.6 %

Procedure:
A solution of methyl iodide (130 g) in acetone (160 ml) was added to a stirred mixture of 2-nitro-4-dodecylacetanilide (196 g) and sodium hydroxide (130 g) in acetone (1100 ml) at room temperature. The mixture was heated rapidly and allowed to boil for 8 minutes, filtered hot and the filtrate evaporated to a semi-solid which was partitioned between toluene (800 ml) and water (400 ml). The organic layer was washed with water, dried and evaporated to give 199 g of 2-nitro-4-dodecyl-N-methylacetanilide as a dark oil.