Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:15]=1[CH:16]=[CH:17][C:18]([OH:20])=[O:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40]([O-:45])(=[O:44])[C:41]([O-:43])=[O:42]>C1C=CC=CC=1>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:12][O:13][C:14]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:15]=1[CH:16]=[CH:17][C:18]([OH:20])=[O:19].[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C([O-])C(=O)[O-]
Agent: COc1ccc(C=CC(=O)O)c(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCCCN1CCCNCC1
Solvent: c1ccccc1
Product: O=C(O)C(=O)O

Procedure:
In 1.50 ml of absolute benzene there were dissolved 1.58 g of 1-homopiperazinepropanol, 3.09 g of 2,3,4-trimethoxycinnamic acid and 9.5 g of p-toluene sulfonic acid. The solution was heated for 16 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate to extract with ether. After the ethereal layer was dehydrated over a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. The liquid was converted into the oxalate thereof in accordance with conventional manner. Upon recrystallization from methanol, 1-homopiperazinepropanol 2,3,4-trimethoxycinnamate oxalate was obtained having a melting point of 156°-158°C. The yield was 48%.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(OC([N:26]1[C:34]2[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=1)=O)(C)(C)C.C([O-])(=O)C.[K+].ClCCl.Br[C:53]1[N:57]([CH3:58])[N:56]=[C:55]([C:59]([NH:61][CH2:62][C:63]2[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=2)=[O:60])[CH:54]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:27]2[NH:26][C:34]3[C:29]([CH:28]=2)=[CH:30][C:31]([C:53]2[N:57]([CH3:58])[N:56]=[C:55]([C:59]([NH:61][CH2:62][C:63]4[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=4)=[O:60])[CH:54]=2)=[CH:32][CH:33]=3)=[CH:37][C:38]=1[CH3:43]
Reactant: Cn1nc(C(=O)NCc2ccc(C(=O)O)cc2)cc1Br
Reactant: Cc1cc(-c2cc3cc(Br)ccc3n2C(=O)OC(C)(C)C)ccc1F
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc3cc(-c4cc(C(=O)NCc5ccc(C(=O)O)cc5)nn4C)ccc3[nH]2)ccc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of bis(pinacolato)diboron (94 mg,0.327 mmol), 5-Bromo-2-(4-fluoro-3-methyl-phenyl)-indole-1-carboxylic acid tert-butyl ester (75 mg, 0.18 mmol), and potassium acetate (55 mg, 55 mmol) in anhydrous 1,4-dioxane (250 uL) is added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (PdCl2(dppf)*CH2Cl2) (45 mg, 0.06 mmol). The reaction mixture is heated under reflux at 100° C. for 2 hours under nitrogen. Under nitrogen, 4-{[(5-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-amino]-methyl}-benzoic acid is added in N,N dimethylformamide (1 ml), followed by aqueous Na2CO3 (1 ml, 2N) and additional catalyst (20 mg). The reaction mixture is heated at 85° C. for 8 hours. The reaction mixture is diluted with 20 ml ethyl acetate, passed through a plug of celite and washed with water. The aqueous layer is evaporated, taken up in TFA/DCM (1:1, 5 ml) and stirred for 30 minutes. The solvent is evaporated in vacuo and the residue purified on reverse-phase HPLC to give the title compound 20 mg, (48%) LC/MS ESI m/z (M+H)+=484.5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[OH:32].[C:33]([NH:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([N:48]=[N:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[C:45]=2[OH:47])[C:40]([S:58](Cl)(=[O:60])=[O:59])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([N:48]=[N:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[C:45]=2[OH:47])[C:40]([S:58]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:12][S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[OH:32])(=[O:59])=[O:60])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: COc1ccccc1N=Nc1ccc2c(S(=O)(=O)Cl)ccc(NC(C)=O)c2c1O
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)c(N)c12
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)c(NS(=O)(=O)c3ccc(NC(C)=O)c4c(O)c(N=Nc5ccccc5OC)ccc34)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 0.85 g (0.0018 mole) crude 1-amino-8-hexadecanesulfonamido-2-naphthol in 16 ml pyridine at 0° C was added 0.81 g (0.0018 mole) 4-acetamido-5-hydroxy-6-(o-methoxyphenylazo)naphthalene-1-sulfonyl chloride. The mixture was stirred overnight at room temperature, then poured in ice water containing 18 ml concentrated hydrochloric acid. The product was dried and triturated first with hot 1:1 dioxaneisopropyl alcohol and then with hot methanol to give 0.85 g of product, m.p. 177°-180° C.
Reaction SMILES: N1CCCC1.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[CH:13]([N:26]1[CH2:29][CH:28]([O:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH:13]([N:26]1[CH2:29][CH:28]([O:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH:13]([N:26]1[CH2:27][CH:6]([N:8]2[CH2:11][CH2:12][CH2:10][CH2:9]2)[CH2:7]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNC1
Product: c1ccc(C(c2ccccc2)N2CC(N3CCCC3)C2)cc1
Temperature: 70 °C
Yield: 125.8 %

Procedure:
Pyrrolidine (142 mg, 2 mmol) and triethylamine (100 mg, 1 mmol) were added to a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (317.4 mg, 1 mmol) in DMF (6 mL). (The methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester was prepared as described in J. Org. Chem. 1991, 56, 6729-6730). The reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was treated with water. The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was then removed under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4) afforded the title compound as an oil (184 mg, 65%). MS: 293 (MH+); HPLC Rf: 5.95 min; HPLC purity: 92%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CC(=O)CC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Yield: 73.5 %

Procedure:
To a solution of 33.0 g (196 mmol) of methyl 2,4-dihydroxybenzoate and 68.0 g (491 mmol) of potassium carbonate mixed in 500 ml of 2-butanone was added 50 ml (235 mmol) of octyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 40.4 g of methyl 2-hydroxy-4-octyloxybenzoate (29) as a colorless clear liquid (yield: 73.5%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 2 L two-necked round bottom flask was charged methyl 4-hydroxybenzoate (100 g, 0.657 mol) and 500 mL of DMF. Potassium carbonate (180 g, 1.3 mol) was added and the mixture was cooled to 0° C. Benzylbromide (77 mL, 0.66 mol) was added dropwise to the reaction mixture with vigorous stirring for 30 min. After the addition was complete, the reaction mixture was stirred for 8 h at RT, then diluted with 500 ml water. The solid precipitated was collected by filtration and washed with water. Drying in a vacuum oven overnight provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:7](=[O:9])[C:6]4[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: COc1ccc(C)cc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 3 h

Procedure:
To a solution of 5-methyl-2-(methyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml), HATU (248 mg, 0.40 mmol) and DIPEA (156 mg, 1.208 mmol) were added. The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol). The reaction was stirred for 3 h then it was loaded onto a PS-aminopropyl cartridge and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen. The residue was dissolved in DMSO and further purified by HPLC using the following conditions:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][C:5]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:4][N:3]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cnc(Br)cn1
Product: N#Cc1ccc(-c2cnc(-c3ccc(C#N)cc3)cn2)cc1
Yield: 52 %

Procedure:
The same procedure described for 1,4-Bis-(2′-cyanopyridin-5′-yl)phenylene was used by employing 2,5-dibromopyrazine and 4-cyanophenylboronic acid to furnish 74 in 52% yield; mp>300° C. (DMF). 1H NMR (DMSO-d6): δ 7.99 (d, J=8.4 Hz, 4H), 8.39 (d, J=8.4 Hz, 4H), 9.42 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7]1)[C:3]([OH:5])=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][O:31][C:32](=[O:34])[N:33]=2)=[CH:25][CH:24]=1.IC1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[OH:1][CH:2]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7]1)[C:3]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)N2CCOC(C(O)C(=O)O)C2)cc1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: FC1(F)CCNCC1
Agent: O=C(O)c1cccc(I)c1
Product: Cc1ccc(S(=O)(=O)N2CCOC(C(O)C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)C2)cc1
Yield: 58.7 %

Procedure:
According to the Step 77-1 in synthetic method for EXAMPLE 77, compound 116-2 (94 mg) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one (79.2 mg) were used instead of 3-iodobenzoic acid and 4,4-difluoropiperidine to obtain compound 116-3 (83 mg) as a pale yellow amorphous solid.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)=[CH:11][CH:10]=1>[OH-].[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[N:16]2[CH3:5])=[CH:11][CH:10]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3)c(=O)c12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 13.7 %

Procedure:
A mixture of dimethyl sulfate (1.1 mL, 11.6 mmol) and (4S,7R)-2-(4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 13; 1.65 g, 5.8 mmol) in 1 M NaOH (25 mL) was heated at 50 degrees overnight, and then allowed to stand at room temperature over the weekend. The precipitate was filtered off, washed with water, and recrystallized from ethyl acetate to give (4S,7R)-2-(4-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (239 mg, 14%) as a white solid. ES(+)-MS (M+H) 301.
Reaction SMILES: C(N[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]#[N:21])(=O)C1C=CC=CC=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]#[N:21]
Reactant: Cl
Reactant: N#Cc1c(NC(=O)c2ccccc2)ccc2ccccc12
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: N#Cc1c(Cl)ccc2ccccc12

Procedure:
33.6 g (0.2 mole) of 2-aminonaphthalene-1-carbonitrile (cf. Example 1) in 250 ml of absolute acetonitrile were added at 65° C. to a suspension of 32.3 g (0.24 mole) of copper(II) chloride (anhydrous) and 30.9 g (0.3 mole) of tert-butylnitrile in 800 ml of absolute acetonitrile. After the end of gas evolution, 2,000 ml of 20% strength hydrochloric acid were added to the cooled reaction mixture, and the precipitate was isolated, washed and dried. 31.7 g (70% of theory) of the title compound of melting point 82°-83° C. (active ingredient example 1001) were obtained in this manner.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([CH2:32][O:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOCc1cccc(Br)c1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
treating the product of step e) with 3-bromo-propoxymethyl-benzene and potassium carbonate to yield (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[N:50]=[C:49]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56](O)=[O:57])[CH:48]=[C:47]([N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[N:46]=1>C(Cl)(Cl)Cl>[Cl:44][C:45]1[N:50]=[C:49]([N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][C:56]2=[O:57])[CH:48]=[C:47]([N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[N:46]=1
Reactant: O=C(O)CCCCNc1cc(N2CCOCC2)nc(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCCN1c1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.8 %

Procedure:
To a solution of HATU (304 mg, 0.8 mmol), HOAT (82 mg, 0.6 mmol) and DIEA (0.209 mL, 1.2 mmol) in chloroform (20 mL) under argon, a solution of 5-(2-chloro-6-morpholinopyrimidin-4-ylamino)pentanoic acid (190 mg, 0.6 mmol) in chloroform (10 mL) was slowly added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was complete, the solution was evaporated to dryness to give a white solid which was chromatographed on a silica gel column by eluting with 40% EtOAc/hexane to give 1-(2-chloro-6-morpholinopyrimidin-4-yl)piperidin-2-one as a white solid (62 mg, 35%). LC/MS (m/z): 297.0 (MH+), Rt 2.74 minutes.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([I:28])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:28])=[C:22]([O:25][CH2:26][CH3:27])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1I
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-iodophenyl)amino]prop-2-enamide (2.0 g, 3.76 mmol) in 100 mL of toluene was heated to reflux and phosphorous oxychloride (3.5 mL, 37.6 mmol) was added dropwise via syringe. This suspension was heated at reflux for 6 hours and additional phosphorous oxychloride (3.5 mL, 37.6 mmol) was added to slowly give a dark solution. After 72 hours the mixture was cooled to room temperature, the solid was filtered and washed with toluene and ether. The light brown solid was dried under reduced pressure at ˜40° C., overnight, to provide 1.47 g (76%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-iodo-3-quinolinecarbonitrile as a yellow solid, mp 213-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (t, 3H, J=6.9 Hz), 4.32 (q, 2H, J=6.9 Hz), 3.88 (s, 3H), 7.53 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H), 8.49 (s, 1H), 9.02 (s, 1H), 11.14 (bs, 1H); MS (ES) m/z514.1 (M+H)+
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: c1ccoc1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and furane
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1Oc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1Oc1ccccc1
Yield: 78.3 %

Procedure:
Prepared according to the procedure of Example 1 using 3-phenoxy-4-methoxybenzoic acid (0.3 g, 1.2 mmol), oxalyl chloride (0.19 g, 1.5 mmol), and aniline (0.22 g, 2.4 mmol) to afford the product (0.3 g); m.p. 200-201° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].C(=O)(OCC)O[CH2:12][CH3:13].[Mg].[Al]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)OCC
Reactant: CCOCCOCCO
Agent: [Al]
Agent: [Mg]
Product: CCOCCOCCOCC
Reaction time: 1 h

Procedure:
Using the apparatus employed in Examples 15-27, a mixture of 2-(2-ethoxyethoxy)ethanol (1 mole) and diethyl carbonate (3 mole) was passed through 11.5 grams of a magnesium:aluminum mixed metal oxide (3/16 inch pellets, Mg/Al 3:1) at a temperature of 225° C. and at a liquid feed rate of 0.29 milliliters/minute. After a period of one hour, a total of 30.2 grams of liquid was collected. Analysis was performed by capillary gas chromatography (FID) using a DB-1701 column. The results were (area %) as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([CH3:19])=[C:17]3[C:12]([C:13]([CH3:21])=[N:14][N:15]=[C:16]3[CH3:20])=[C:11]2[CH3:22])=[C:6]([CH:23]=[CH2:24])[CH:5]=1)[CH3:2].NN>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]([CH3:22])=[C:12]3[C:17]([C:16]([CH3:20])=[N:15][N:14]=[C:13]3[CH3:21])=[C:18]2[CH3:19])=[C:6]([CH2:23][CH3:24])[CH:5]=1)[CH3:2]
Reactant: C=Cc1cc(OCC)ccc1-n1c(C)c2c(C)nnc(C)c2c1C
Agent: NN
Solvent: CCO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(CC)c1
Temperature: 90 °C

Procedure:
To a solution of 6-(4-ethoxy-2-vinyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine (30 mg, 3.0 mmol) in 3 mL of ethanol was added anhydrous hydrazine (20 μL). The resulting reaction solution was refluxed at 90° C. for 90 min. It was allowed to warm to rt and directly condensed in vacuo to afford 6-(4-Ethoxy-2-ethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as a light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.00 (m, 2H), 6.89 (m, 1H), 4.15 (q, 2H), 2.82 (s, 6H), 2.38 (s, 6H), 2.10 (q, 2H), 1.52 (t, 3H), 1.08 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[CH2:7]1[CH:16]2[CH:11]([CH2:12]CCC2)[CH2:10][CH2:9][C:8]1=O.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:2]1[CH2:4][CH2:12][CH:11]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:16]2)[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2CCCCC2C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1CCC2CCCCC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyltriphenylphosphonium bromide (89.2 g, 249 mmol) was placed in abs. diethyl ether (800 ml) under a nitrogen atmosphere. At 0° C. potassium tert-butylate (34 g, 295 mmol) was slowly added. After 30 min octahydronaphthalen-2-one (25 g, 164 mmol) as a solution in diethyl ether (500 ml) was slowly added dropwise, again at 0° C. The reaction mixture was stirred overnight at RT. For working up, the reaction mixture was cooled in an ice bath and mixed with sat. aq. NH4Cl solution. The phases were separated and the aqueous phase was shaken out several times with EtOAc. The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The residue was taken up in hexane/ether 1:1, removed by suction-filtration and the residue washed with hexane/ether 1:1. The filtrate was concentrated and the residue also removed by suction-filtration. The desired compound 2-methylenedecahydronaphthalene was obtained as a solid (16.3 g, 66% of the theoretical amount).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (s)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.