Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][CH2:36]Br)(=[O:33])[CH3:32]>CN(C)C=O>[C:31]([O:34][CH2:35][CH2:36][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Temperature: 60 °C
Reaction time: 11 h
Yield: 84.9 %

Procedure:
To a solution of 40 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine in 300 ml of dimethylformamide are added 34,2 g of potassium carbonate and 31 g of 2-acetoxyethyl bromide, and the mixture is stirred at 60° C. for 11 hours. The resulting mixture is poured into ice-cold water and the precipitate is extracted with ethyl acetate and then the extract is washed with water, dried and concentrated. The resulting residue is recrystallized from isopropyl alcohol to give 43 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 115°-116° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CCl)cc1
Reactant: C1COCCN1
Solvent: O
Product: CC(=O)Oc1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
To 4-(chloromethyl)phenyl acetate (2.5 g, 13.5 mmol) was added neat morpholine (3.0 mL, 34.4 mmol) at r.t. The solution was heated to 70° C. for 45 min, then cooled. Water (10 mL) was added and the solution was extracted with 10% methanol in dichloromethane (4×20 mL). The combined organics were washed with brine, dried with Na2SO4, and concentrated. Purification on silica gel (10% methanol/dichloromethane) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:24])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.[NH4+].[Cl-]>[Fe]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][NH:14][C:15](=[O:24])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(CN1CCC(O)CC1)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Oc2ccncc2C#CCNC(=O)CN2CCC(O)CC2)c(F)c1

Procedure:
The title compound was prepared by the reduction N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(4-hydroxypiperidin-1-yl)acetamide (33 mg, 0.077 mmol) in a manner similar to that of Step E of Example 35 using Fe (powder, 67 mg, 1.21 mmol), NH4Cl (128 mg, 2.42 mmol). The product (30 mg, 100%) was obtained as a yellow oil which was used directly in the subsequent step. MS(ESI+): m/z 399.27 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:16])=[N:13]2)=[CH:8][CH:7]=1.[O:17]1CCOCC1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:16]=[O:17])=[N:13]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2ccc(C)nc2c1
Reactant: C1COCCO1
Solvent: O
Product: COCCOc1ccc2ccc(C=O)nc2c1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-2-methylquinoline (235 mg, 1.08 mmol) in dioxane (3 mL) and water (0.03 mL) was added SeO2 (132 mg, 1.19 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-methoxyethoxy)quinoline-2-carbaldehyde (195 mg, 78%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([N:36]([CH3:38])[CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([N:36]([CH3:38])[CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-n-propyl-4-methyl-6-(2-cyano-3,3-dimethyl-guanidino)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][CH2:3]1.O1CCOC[CH2:17]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:17][O:14][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][S:6][C:7]=2[CH:12]=1)=[O:15]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccc2c(c1)SCCCC2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)SCCCC2=O
Temperature: 25 °C

Procedure:
This 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid (3.42 g) was dissolved in methanol (100 ml) and 4N hydrochloric acid dioxane solution (15 ml) was added. The mixture was stirred under reflux for 3 hr. The reaction mixture was cooled to room temperature and saturated aqueous sodium hydrogencarbonate solution (250 ml) was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the objective 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (3.35 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10]C(=O)C.CC(O)=O.[N:18](OCCC(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([CH3:9])[CH:5]=1)[NH:10][N:18]=[CH:1]2
Reactant: CC(=O)Nc1c(C)cc(C)cc1C
Reactant: CC(C)CCON=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)c2[nH]ncc2c1
Yield: 100.3 %

Procedure:
N-(2,4,6-trimethyl-phenyl)-acetamide (23.8 g, 133 mmol) (prepared as described in Example 12) was dissolved in a mixture of toluene (300 mL) and glacial AcOH (10.4 g, 173 mmol, 1.3 eq) and then treated slowly with isoamyl nitrite (20.3 g, 23.2 mL, 173 mmol, 1.3 eq). The mixture was heated at reflux overnight or until all the starting material was consumed as judged by TLC (30% EtOAc-hexanes). The solution was then poured into H2O (1.3 L) and extracted with EtOAc (2×300 mL). The combined organic extracts were then washed with saturated aq. NaHCO3 solution (2×200 mL) and brine (1×100 mL). The extracts were dried (MgSO4), filtered, and concentrated to provide 19.5 g of 5,7-dimethyl-1H-indazole 2 as a red waxy solid. This material was carried on without additional purification. RP-HPLC Method: 2-100% B in 2 minutes
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:35][N:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCOCC2)cn1
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.442 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.142 g, 17.6%). MS (APCI); M++1: Calc'd, 451.3. Found 451.3. Anal. Calc'd for C25H32N6O2: C, 63.98; H, 6.71; N, 18.65. Found: C, 64.03; H, 6.66; N, 18.49.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[N:18]([S:21]([C:24]5[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[CH:19]=[CH:20][C:13]=34)=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:31][C@@H:32]1[CH2:37][NH:36][CH2:35][CH2:34][NH:33]1.C(N(CC)CC)C>C(O)CCCC.Cl>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:36]3[CH2:35][CH2:34][NH:33][C@H:32]([CH3:31])[CH2:37]3)=[N:7][N:6]2[C:8]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:13]=12
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5ccc(Cl)nn45)ccnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 0.325 g (0.97 mmol) of 6-chloro-2-methyl-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.15 g (1.5 mmol) of (2R)-2-methylpiperazine and 0.10 ml (0.74 mmol) of triethylamine in 5 ml of pentanol is heated under reflux for 3 days at 150° C. The reaction medium is diluted with 100 ml of a 1N aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown oil obtained is then chromatographed over a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) in order to give 0.293 g of 2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow oil after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:16]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(N=O)c1
Reaction time: 72 h
Yield: 34 %

Procedure:
To a stirred solution of 3-aminobenzamide (Aldrich Chemical Co.) (0.476 g, 3.50 mmol) in ethyl acetate (50 ml) at ambient temperature was added 1.208 g of 3-chloroperoxybenzoic acid (commercial grade, 50-60% purity, Aldrich), whereupon the solution turned green. After 10 minutes the mixture was extracted with 0.14M aqueous sodium bicarbonate (58 ml), washed with three successive 40-ml portions of water, dried over sodium sulfate, then reduced in volume to 20 mL by rotary evaporation and placed in the freezer (-20° C.), whereupon the product slowly deposited as a light yellow solid during a period of 72 hours (0.180 g, 34% yield).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(OCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
To an acetic acid (2.5 mL) and dimethyl sulfoxide (43 mL) solution of 2-(3-((E)-2-nitro-vinyl)-phenoxymethyl)-pyridine (2.56 g, 10 mmol) described in Manufacturing Example 60-1-2 was added sodium borohydride (605 mg, 16 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1-4:1-1:1) to obtain the title compound (1.66 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To methyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate (Example 2) (0.2 g, 0.55 mmol) dissolved in EtOH (5.5 mL) was added aqueous KOH (0.6 mL, 5.5 M). The reaction mixture was stirred at room temperature for 1 h. The solvent was then removed under reduced pressure and the crude product dissolved in water. The aqueous phase was acidified using conc. HCl so that the product precipitated. Filtration and washing with water (5 mL) afforded 0.2 g, 97% product. The product was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:36]=[C:5]2[N:6]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CO.[BH4-].[Na+]>O1CCCC1>[OH:35][CH:32]1[CH2:33][CH2:34][CH:29]([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:36]=[C:5]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g), methanol (15 mL) and tetrahydrofuran (15 mL) was added sodium borohydride (0.24 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.8 g, 90%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CS(O[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])(=O)=O>CN(C=O)C>[CH3:13][C:5]([CH3:14])([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][O:3][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41]
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
Sodium hydride (60% wt in oil) (400 mg, 10 mmol) was added to a stirred solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (57) (1.74 g, 10 mmol) in DMF (20 mL) at 0° C., after 30 min a solution of 2,5,8,11,14,17,20-heptaoxadocosan-22-yl methanesulfonate (2.79 g, 6.67 mmol) in DMF (10 mL) was added dropwise, and the reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with DCM (2×100 mL), the combined organic layers were washed with brine (3×100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (120 g, 0-10% MeOH in EtOAc) to afford tert-butyl 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (58) (1.59 g, 48%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.65-3.51 (m, 32H), 3.40 (s, 2H), 3.36 (s, 3H), 1.41 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][CH:4]=1)[CH3:12]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(SC)cc1
Product: CCOC(=O)C=CC#Cc1ccc(SC)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methylsulfanyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (450 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (d, J=8.5, 2H), 7.18-7.16 (d, J=8.5, 2H), 6.35-6.32 (d, J=11.4, 1H), 6.11-6.09 (d, J=11.4, 1H), 4.28-4.22 (q, J=7.1, 2H), 2.46 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.81, 140.87, 132.33, 127.85, 125.68, 122.81, 118.84, 101.21, 86.77, 60.37, 15.16, 14.32. Anal. Calcd. for C14H14O2S: C, 68.26; H, 5.73; S, 13.02; Found C, 68.50; H, 5.88; S, 13.18.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:26])[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:27]>CO.O>[CH3:26][C:13]1[N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:27])[C:11]=2[N:12]=1
Reactant: N
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Solvent: CO
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (1.80 g, 4.55 mmol) in a solution of ammonia in methanol (7 M, 18 mL) in a high pressure vessel was heated at 150° C. for 14 hours. The vessel was allowed to cool to room temperature. A solid was isolated by filtration, washed with methanol, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was stirred in water (100 mL) for 1 hour, isolated by filtration, washed with water, and dried to yield 0.84 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 253-255° C.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:16][NH3+:17]>C(O)C>[CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:17][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: O=C1CCCCC1=Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: ON=C1CCCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
A mixture of 2-benzylidenecyclohexanone (3.5 g, 18.8 mmol, J. Chem. Soc. 1949, 2957), hydroxylammonium chloride (3.9 g, 56 mmol) and ethanol (50 ml) was stirred at ambient temperature for 3 days. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate (200 ml) and water (50 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated in vacuo to give 3.7 g of 2-benzylidenecyclohexanone oxime as a solid. M.p. 114°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(C)(C)[CH2:25][OH:26].C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:26][CH3:25])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)CO
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (1.2557 g, 3.30 mmol), 2,2-dimethylpropan-1-ol (0.914 g, 10.37 mmol), 18-crown-6 (0.087 g, 0.330 mmol), and potassium hydroxide (0.925 g, 16.50 mmol) (freshly ground). The vial was flushed with Ar (g), then dioxane (6.60 mL) was added. The vial was sealed and placed in a 120° C. oil bath and stirred for 24 hours. The reaction mixture was diluted with water and a small amount of brine. The aq. mixture was then extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc/hexanes) to afford 0.657 g of (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a yellow solid. Step 2: A microwave vial was charged with (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.065 g, 0.173 mmol), 2-fluoropyridin-3-ylboronic acid (0.049 g, 0.346 mmol), potassium phosphate (0.110 g, 0.518 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.12 mg, 8.64 μmol). The vial was flushed with Ar (g), dioxane (0.648 mL) and water (0.216 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/EtOAc) to afford 65 mg of (S)-7-(2-fluoropyridin-3-yl)-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light yellow solid.