Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:35](O)(=[O:37])=[O:36])[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.S(Cl)(Cl)=O.Cl.[Cl-].[NH2:45][CH2:46][CH2:47][C:48]1[CH:49]=[N+:50]([CH3:54])[CH:51]=[CH:52][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N.CN(C=O)C>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:35]([NH:45][CH2:46][CH2:47][C:48]2[CH:49]=[N+:50]([CH3:54])[CH:51]=[CH:52][CH:53]=2)(=[O:36])=[O:37])[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:16])[CH3:17])=[CH:13][N:14]=1
Reactant: C[n+]1cccc(CCN)c1
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCc4ccc[n+](C)c4)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a suspension of 3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)benzenesulfonic acid (250 mg, 0.43 mmol) in DCM (5 mL) was added thionyl chloride (1 mL) and DMF (10 uL, anhyd). The reaction mixture was heated 2 h at 50° C., concentrated, diluted with DCM, and concentrated to dryness. The sulfonyl chloride intermediate was diluted with DCM (3 mL) and added slowly to a well-stirred mixture of 3-(2-aminoethyl)-1-methylpyridinium chloride hydrochloride (100 mg, 0.58 mmol) and K2CO3(178 mg, 1.29 mmol) in CH3CN (10 mL). After stirring 2 h, the reaction mixture was filtered and concentrated. The residue was purified by chromatography (10-20% MeOH/DCM) to afford the title compound as a solid (18 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.77 (s, 1H), 8.40-8.32 (m, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.51 (d, J=8.29 Hz, 1H), 7.15 (s, 1H), 6.96-6.78 (m, 3H), 6.62-6.38 (m, 5H), 4.54 (s, 3H), 4.03 (s, 2H), 3.77 (s, 4H), 3.52-3.41 (m, 4H), 3.22-3.12 (m, 2H), 1.82-1.58 (m, 6H), 1.50 (s, 7H), 1.21 (t, J=7.02 Hz, 4H); MS (EI) m/z 701 [M]+.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:8]=1[CH3:28])C.FC(F)(F)C(O)=O.[NH:39]([C:41]1[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[N:45][CH:46]=1)[NH2:40].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:47]([C:44]1[N:45]=[CH:46][C:41]([N:39]2[C:6]([C:7]3[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[C:8]=3[CH3:28])=[CH:5][CH:4]=[N:40]2)=[CH:42][CH:43]=1)#[N:48]
Reactant: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Reactant: N#Cc1ccc(NN)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)nc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 28.2 %

Procedure:
Methyl 6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.073 g, 0.17 mmol) and 5-hydrazinopyridine-2-carbonitrile trifluoroacetate (0.050 g, 0.20 mmol) in dioxane (3 ml) were placed in a vial. 2M HCl (0.188 ml) was added and the mixture was stirred at 55° C. for 15 min. After cooling, NaHCO3 (0.048 g) was added and the mixture was extracted with DCM and water. The combined organic phases were washed with water, brine, dried (Na2SO4) and evaporated. The residue was dissolved in acetic acid (10 ml) and the vial was sealed. The solution was stirred at 90° C. for 10 h. After evaporation, the residue was purified by preparative HPLC to give 0.023 g (28%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1.[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[CH2:46][C:47](O)=[O:48].C([O-])(O)=O.[Na+]>>[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[CH2:46][C:47]([NH:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[C:15]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[C:8]=23)=[C:4]([F:36])[CH:3]=1)=[O:48]
Reactant: O=C(O)Cc1nc2ccccc2o1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)Cc5nc6ccccc6o5)cc4F)c23)CC1
Yield: 80 %

Procedure:
Prepared by a 2-step process from 1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (prepared as in Example 93, Step A) and 2-(benzo[d]oxazol-2-yl)acetic acid according to the procedure of Example 21, Steps A and B, except that the crude was treated with aqueous NaHCO3 solution to remove TFA. The crude was rinsed with Et2O to afford 13 mg (80%) of the desired product. LRMS (ESI pos) m/e 530.1 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.20 (d, 1H), 7.86 (dd, 1H), 7.72 (m, 1H), 7.60 (m, 1H), 7.41 (m, 3H), 7.30 (t, 1H), 6.22 (d, 1H), 4.15 (m, 2H), 2.95 (t, 3H), 2.64 (s, 6H), 2.09 (m, 2H), 1.84 (m, 2H); 19F-NMR (376 MHz, CD3OD/CDCl3) δ −128.7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(F)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To 2-chloro-4,5-difluoro-benzoic acid (118, 14.0 g, 0.0727 mol) in methanol (100 mL) was added sulfuric acid (concentrated, 98%, 2.00 mL, 0.0375 mol). The reaction was stirred at 60° C. for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:20][CH2:19][CH2:17][OH:18])[CH:4]=2)=[CH:11][CH:12]=1
Reactant: NCCO
Reactant: Clc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccc(Cl)cc2)ncn1
Temperature: 200 °C
Yield: 67 %

Procedure:
75 mg of 6-chloro-N-(4-chlorophenyl)pyrimidin-4-amine hydrochloride, 18 mg of ethanolamine and 87 mg of DIPEA were dissolved in n-BuOH (1 mL) and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(4-Chlorophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].Cl.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=[NH:27])[NH2:26].C([O-])(O)=O.[Na+].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:26]=[C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[NH:27][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c[nH]c2c1-c1nc(-c3ccncc3)[nH]c1CCC2
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H) 8.28 (br s, 1H) 8.56 (d, 2H)
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=O.[O:5]=[CH:6][C@H:7]([CH2:9][OH:10])[OH:8].[CH2-]C(C)=O.COC1C=C(OC)C=CC=1CN=C(C)[CH2-].[O:30]=[CH:31][C@H:32]([CH2:34][OH:35])[OH:33]>>[CH3:1][C:2]1([CH3:4])[O:8][CH:7]([CH:9]2[O:10][C:31](=[O:30])[C:32]([OH:33])=[C:34]2[OH:35])[CH2:6][O:5]1
Reactant: [CH2-]C(C)=O
Reactant: O=C[C@@H](O)CO
Agent: [CH2-]C(C)=NCc1ccc(OC)cc1OC
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1

Procedure:
In 400 ml of pure water was suspended 43.2 g of 5,6-O-isopropylidene-L-ascorbic acid, and 40 g of calcium carbonate was added. The mixture was cooled and 80 ml of 30% aqueous hydrogen peroxide was added dropwise while maintaining the temperature at 10° C. or below. Thereafter, the temperature was raised to 20° C. over a period of an hour, followed by stirring at the same temperature for 2 hours and at 30° to 35° C. for 30 minutes. To the reaction mixture were portionwise added 8 g of activated carbon and 1 g of 10 w/w % palladium-on-carbon (50 w/w % hydrous) to treat the unreacted hydrogen peroxide therewith and the mixture was cooled, followed by removal of the insoluble substance with the aid of Hyflo Super-Cel to give 650 ml of an aqueous solution containing CIT. Thereafter, according to the procedure of Example 2 there was synthesized (S)-glyceraldehyde acetonide and the acetonide was then converted to (S)-glyceraldehyde acetonide 2,4-dimethoxybenzylimine. The yield of the imine was 39.3 g (70% overall yield from 5,6-O-isopropylidene-L-ascorbic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])N.C(C1C=C(C=C(C(O)=O)C=1)[NH2:20])(O)=O>>[CH3:1][O:2][CH:3]1[CH:9]([O:10][CH3:11])[CH:8]([O:12][CH3:13])[CH2:7][CH2:5][CH:4]1[NH2:20]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COC1CCC(N)C(OC)C1OC

Procedure:
3,4,5-trimethoxyaniline was hydrogenated via the procedure given for 3,5-dicarboxy-aniline to provide 2,3,4-trimethoxycyclohexylamine which was coupled to the C-terminal valine in the standard way.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 67.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(2-methoxyphenyl)piperazine (97 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[1-(2-methoxyphenyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 41) (142 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 50 °C
Yield: 52.1 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the solution was heated at 50° C. overnight under nitrogen. The solvents were evaporated under reduced pressure and the resulting oil was partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (50 ml). The combined organic layers were washed once with water (50 ml) followed by two (50 ml) portions of 5% potassium hydroxide solution and then by water again (50 ml). The organic layer was dried over magnesium sulfate, charcoaled, filtered and evaporated to an oil which was crystallized from hot isopropyl ether. The solid was collected by filtration, and dried under high vacuum at room temperature to give 3.33 g (52%) of title compound, mp 96°-99° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][Li])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]OC(=O)CCCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)O
Yield: 94.9 %

Procedure:
To a solution of 4-[tert-butyl(dimethyl)silyl]oxybutanoyloxylithium (8.0 g, 35.71 mmol) in ethyl acetate (10 mL), was carefully added KHSO4 (5%) to adjust pH to about 1. It was then extracted with ethyl acetate three times and organic extracts washed with brine and dried with anhydrous NaSO4. The organic extracts were concentrated to give the title compound (7.4 g, 95%). [M+H] Calc'd for C10H22O3Si, 219. Found, 219.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.C1CCN2C(=NCCC2)CC1.C(#N)C>ClCCl.O>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:22]=1)[C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:23]=2
Reactant: Cc1ccc(N)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc2ccc(C)cn2c1=O
Temperature: 150 °C
Yield: 53.8 %

Procedure:
A mixture of diethyl 2-(ethoxymethylene)malonate (0.60 g, 3 mmol), 5-methylpyridin-2-amine (0.20 g, 2 mmol), DBU (0.1 ml, 0.9 mmol) in acetonitrile (2 g, 49 mmol) was heated under Microwave (CEM) at 150° C. (150 W) for 20 min. The resultant was diluted with dichloromethane and water, and the organic layer was dried over sodium sulfate. The organic solution was concentrated, and the residue was crystallized in dichloromethane and diethyl ether to give the title compound as a pale yellow solid (0.25 g, 58%): MS (ESI pos. ion) m/z: 233 (MH+). Calc'd exact mass for C12H12N2O3: 232.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]2)[C:23]([F:26])([F:25])[F:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)[C:23]([F:25])([F:26])[F:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(N4CCC(C(=O)O)CC4)C(F)(F)F)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(1-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-2,2,2-trifluoroethyl)piperidine-4-carboxylate (100 mg, 0.2 mmol) in MeOH (5 mL) was added NaOH (32 mg, 0.8 mmol, 4.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. Then the reaction was cooled to 0° C., and the pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtered, and the yellow solid was the desired product 1-(1-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-2,2,2-trifluoroethyl)piperidine-4-carboxylic acid (78 mg, yield: 80%). ESI-MS (M+1)+: 492.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:13]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:13]=2[N:21]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825 mmol) in DMF (2.500 ml) was added NaH (0.041 g, 55% dispersion in mineral oil, 0.945 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C., followed by the addition of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.15 g, 0.750 mmol). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (0.09 g, 43%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.12 (2H, m), 2.17-2.21 (2H, m), 2.22-2.32 (2H, m), 2.34 (3H, s), 2.84-2.89 (2H, m), 5.38-5.45 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Li+:23].NC(N)=O.NC(OCC)=O>>[OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14].[Li+:23]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: CCOC(N)=O
Agent: NC(N)=O
Agent: [Li+]
Product: CCCCCCC(O)CCCCCCCCCCC(=O)[O-]

Procedure:
12-hydroxystearic acid was reacted with lithium hydroxide in a mole ratio of 1:1 under heating in a proper amount of the same refined mineral oil as one used in the preparation of urea-urethane base grease A to obtain lithium 12-hydroxystearate, and then the obtained lithium 12-hydroxystearate was dispersed in such an amount of the refined mineral oil as to give a lithium 12-hydroxystearate content of 8% by mass based on the total amount of the lithium soap base grease C.
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1(O)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30].[Cl-:32].[NH4+]>ClCCl>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1([Cl:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30]
Reactant: [Cl-]
Reactant: O=C1Nc2ccc(Cl)cc2C1(O)c1nc2ccccc2s1
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C1(Cl)c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.57 ml) and thionyl chloride (0.42 ml) were successively added to an ice-cooled solution of the intermediate from Step A (1.27 g, 4.0 mmol) in dichloromethane (40 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:5][CH:4]=1.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]>>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:12][CH:11]([CH2:10][C:9]2[C:16]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:17]=3)[NH:7][CH:8]=2)[C:13]([OH:15])=[O:14])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: COc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(OC)cc23)C(=O)O)cc1

Procedure:
The title compound was prepared by the method of Example 6, using 5-methoxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. 1H NMR (DMSO-d6): 400 MHz δ 12.55 (bs, 1H), 10.63 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 2H), 6.82 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.0, 2.0 Hz, 1H), 4.78 (q, J=2.0 Hz, 2H), 3.87 (q, J=7.6 Hz, 1H), 3.72 (s, 3H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.82 (dd J=14.4, 7.6 Hz, 1H), 1.83 (t, J=2.0 Hz, 3H); HRMS: calcd for C22H24N2O6S (ESI+, [M+H]1+), 443.1271; found 443.1265; LCMS m/z (ESI) [M+H] 443, retention time=2.50 min.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.OO>O.CN(C)C=O>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]([NH2:31])=[O:2])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of potassium carbonate (96 mg, 0.69 mmol) in water (0.5 mL) was added to 2-{[6-(2,4-difluorophenyl)-2-naphthyl]sulfonyl}benzonitrile (Example 2, 138 mg, 0.34 mmol) in N,N-dimethylformamide (6 mL). Hydrogen peroxide (35 wt %, 120 μL, 1.37 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (60 mL). The resulting precipitate was collected by filtration and recrystallised from ethyl acetate/isohexane to give the title compound (118 mg, 82%). 1H NMR (500 MHz, d6-DMSO) δ 8.68 (1H, s), 8.22 (1H, d, J=8.6 Hz), 8.16 (3H, dd, J=6.9, 15.7 Hz), 8.02 (1H, d, J=8.8 Hz), 7.98 (1H, s), 7.81 (1H, d, J=8.5 Hz), 7.75-7.69 (2H, m), 7.66 (1H, t, J=7.2 Hz), 7.60 (1H, s), 7.47 (1H, d, J=7.2 Hz), 7.45-7.39 (1H, m), 7.27-7.23 (1H, m); m/z (ES+) 407 [(M-NH2)+]