Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
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: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5cccc(Cl)c5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (1.1 g, 2.81 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.903 g, 3.65 mmol), Na2CO3 (0.745 g, 7.03 mmol) and Pd(PPh3)4 (0.325 g, 0.281 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 mL) and concentrated to afford the crude title compound (310 mg) as a yellow solid. LC-MS (ES) m/z=476 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH2:24][C:25]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:27](=[CH:28][N:29]([CH2:35][O:36][CH3:37])[N:30]=4)[CH:26]=3)[CH2:22][OH:23])=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@H:21]([CH2:24][C:25]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:27](=[CH:28][N:29]([CH2:35][O:36][CH3:37])[N:30]=4)[CH:26]=3)[CH:22]=[O:23])=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(CC(CO)OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)cc(C)c2n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCn1cc2cc(C[C@H](C=O)OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)cc(C)c2n1
Temperature: 5 °C
Reaction time: 0.02 h

Procedure:
1-Hydroxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (0.65 g, 1.29 mmol) was dissolved in anhydrous dimethyl sulfoxide (5.0 mL). Triethylamine (0.54 mL, 3.87 mmol) was added and the reaction mixture cooled to ca. 5° C. using an ice bath. A solution of sulfur trioxide pyridine complex (0.62 g, 3.87 mmol) in dimethyl sulfoxide (4.0 mL) was added in one portion. After 1 min, the ice bath was removed and the reaction mixture stirred at room temperature for 20 min. The reaction mixture was poured into an ice slurry and extracted with ethyl acetate (3×). The combined organic extracts were washed with 10% citric acid (2×), water (2×), 5% sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 0.55 g (85%). 1H-NMR (DMSO. d6, 500 MHz) δ 1.90 (s, 3H), 2.48 (s, 3H), 2.51 (m, 2H), 2.71-2.95 (m, 4H), 4.51 (m, 1H), 4.72-4.84 (m, 1H), 6.31-6.46 (m, 1H), 6.91 (d, J=4.0, 1H), 8.36 (s, 1H), 11.74 (s, 1H). Mass spec.: 503.3 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([NH:14][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCCCC(=O)O
Reactant: CCCCCCN
Product: CCCCCCNC(=O)CCCN

Procedure:
As above using 4-aminobutyric acid in place of glycine and n-hexylamine in place of n-heptylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][CH2:13]Cl)=[O:11].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1>C(O)C>[CH3:15][C:16]1[N:20]([CH2:13][CH2:12][C:10](=[O:11])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Reactant: CC1=NCCN1
Solvent: CCO
Product: CC1=NCCN1CCC(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Ex. IA react 5.29 gm. (0.025 M) of 3-chloro-2',6'-propionoxylidide with 10.53 gm. (0.125 M) of lysidine in 200 ml. of anhydrous ethanol to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C:41]([C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[NH:42])=[O:39])([CH3:36])[CH3:35]>>[NH:42]=[C:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:35])([CH3:33])[CH3:36])[C:43]1[CH:44]=[CH:45][C:46]([C:47]([N:15]2[CH2:16][C@@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([O:30][CH3:31])=[O:32])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:48])=[CH:50][CH:51]=1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(C(=N)NC(=O)OC(C)(C)C)cc3)[nH]2)cc1

Procedure:
The compound prepared in Example 66 was treated with the compound prepared in Example 18 following the procedure described in Example 8 to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:16])[C:2]#[C:3][CH3:4].Cl[CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1=[O:16])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(=O)n(COC(=O)C(C)(C)C)c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(2-Butynyl)-2,6-dichloro-7,9-dihydropurin-8-one (compound 1d) (193 mg) was dissolved in N,N-dimethylformamide (2 mL), and then 2,2-dimethylpropionic acid chloromethyl ester (163 μL) and anhydrous potassium carbonate (156 mg) were added to this solution. After stirring the reaction solution at room temperature for 18 hours, saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution. This was then extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and then saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (434 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23].[BH4-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O1CCCC1.O>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: COC(=O)CCCCCCCCCc1c(C)cc(OC)c(OC)c1O
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Temperature: 15 °C
Yield: 99.2 %

Procedure:
In tetrahydrofuran (1.8 l) was dissolved methyl 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoate (881 g, 2.5 mol.). To the solution was added a suspension of sodium borohydride (340 g, 9 mol.) in tetrahydrofuran (10.7 l), and the mixture was stirred. To the resulting suspension was added water (75 ml, 4.16 mol.). Aluminum chloride (400 g, 3 mol.) was dissolved in tetrahydrofuran (6.0 l). The solution was added dropwise to the above-mentioned suspension at a given rate in the course of 90 minutes, during which period the inner temperature of the reaction mixture was kept at 25±2° C. Then, the reaction mixture was stirred at the same temperature for further 30 minutes, which was then cooled to about 15° C. To the reaction mixture was added water (22 l) dropwise to cause decomposition, to which was then added dropwise hydrochloric acid (2.7 l). The mixture was subjected to extraction twice with 9 l each portion of toluene. Then, the toluene layers were combined and washed with a 5% aqueous solution of sodium hydrogen carbonate (4.4 l), followed by further washing with water (4.4 ). The toluene layer was concentrated under reduced pressure to obtain 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (805 g, 2.48 mol., yield 99.2%) as an oily product.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[N:7]=[CH:6][C:5]=1[C:14]([O:16]CC)=[O:15]>O>[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[N:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2cccnc2c1O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 8.0 g. (0.2 mol.) of sodium hydroxide in 200 ml. of water is added 20.0 g. (0.0917 mol.) of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate. The mixture is heated under reflux for 6 hours, and then the hot solution is treated with decolorizingcharcoal and then filtered hot. The filtrate is cooled to 25° C. andacidified to pH 3 with 6N hydrochloric acid. The mixture is then cooled in an ice-bath for 15 minutes and the precipitate is removed by filtration. The solid obtained is washed with water, followed by ether, followed by acetone, and dried. This affords 11.2 g. (64% yield) of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC(F)(F)C[C@@H]1c1ccnn1C
Yield: 97.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (80.0 mg, 0.13 mmol) prepared in Example 126a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (61.0 mg, 99%) as a colorless solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O.[NH3:16].O.Cl>O1CCCC1>[F:14][C:8]1[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH2:16])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
A solution of 5-chlorosulfonyl-2-fluorobenzoic acid (7.0 g) and 28% ammonia water (20 ml) in tetrahydrofuran (70 ml) is stirred at 0° C. for 1.5 hours. The reaction mixture is poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted with chloroform. The extracts are washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is washed with diethyl ether to give the title compound (5.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:16][C@H:17]1[CH2:23][CH2:22][CH2:21][C@H:20]([CH3:24])[CH2:19][NH:18]1.[Cl-].[NH4+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH2:19][C@@H:20]([CH3:24])[CH2:21][CH2:22][CH2:23][C@@H:17]2[CH3:16])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[C@H]1CCC[C@H](C)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C[C@H]1CCC[C@H](C)N(c2cc(Cl)ncn2)C1
Temperature: 6 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into 3 ml of acetonitrile were added 0.2 g of 4,6-dichloropyrimidine, 0.56 g of potassium carbonate and 0.31 g of trans-2,6-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 2 hours at 6° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 1-(6-chloropyrimidin-4-yl)-trans-2,6-dimethylhexahydro-1H-azepine.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.O.[OH-].[Li+].CO>C1COCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-4-ylmethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (118 mg, 0.36 mmol) and lithium hydroxide monohydrate (60 mg, 1.42 mmol in 5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (15 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-70% EtOAc/Heptane to give the title compound: 60 mg, 53%. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.06-2.18 (m, 1H), 2.48-2.62 (m, 1H), 2.62-2.75 (m, 2H), 2.78-2.89 (m, 2H), 3.28-3.37 (m, 1H), 6.37 (d, J=1.76 Hz, 1H), 7.29-7.37 (m, 3H), 7.41-7.48 (m, 2H), 7.57-7.63 (m, 2H), 7.63-7.69 (m, 2H), 10.38 (s, 1H); LCMS-MS (ESI−) 316.2 (M−H); HPLC (UV=99.4%), (ELSD=100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[OH-].[Li+].Cl>C1COCC1>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:14][CH2:15]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)OC)CC5)cc4s3)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)O)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.2 %

Procedure:
To a solution of methyl 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (Compound 47A, 268 mg, 0.447 mmol) in THF (3 mL) was added sat. aq. lithium hydroxide (1 mL). The reaction mixture was stirred at rt for 6 h. The reaction mixture was neutralized with cool aq. HCl (1 N) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was recrystallized from 10% water in CH3CN to afford 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoic acid (218 mg, 0.354 mmol, 79% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.25 (br. s., 2H), 7.60-7.66 (m, 2H), 7.39 (dd, J=8.5, 1.9 Hz, 1H), 6.01-6.12 (m, 1H), 5.43-5.53 (m, J=7.3, 3.6, 3.6, 3.4 Hz, 1H), 4.17-4.28 (m, 2H), 3.98-4.07 (m, 2H), 3.60 (t, J=5.8 Hz, 2H), 3.07-3.15 (m, 2H), 2.68 (d, J=1.7 Hz, 2H), 2.58-2.64 (m, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.10-2.26 (m, 5H), 1.95-2.08 (m, 2H), 1.50-1.66 (m, 4H), 0.96 (t, J=7.4 Hz, 3H). LCMS (m/z)=586 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:33]3[CH2:38][CH2:37][O:36][CH2:35][CH:34]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2C2=CCOCC2)C1
Yield: 80 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (1.0 g, 3.7 mmol) in dioxane (16 mL) was added a solution of Na2CO3 (780 mg, 6.4 mmol) in 5 mL water, followed by additional of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (114) (purchased from WUXI APPTEC) (840 mg 4.0 mmol) and Pd(dppf)Cl2 (80 mg). The resulting mixture was heated to reflux overnight under N2 atmosphere. TLC showed that the staring material was consumed completely. The solution was filtered and the filtrate was concentrated to give the residue which was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give the product 3-[3-(3,6-dihydro-2H-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylic acid tert-butyl ester (115) (938 mg, 2.96 mmol, yield 80%) as solid. ESI-MS (M+1): 318 calc. for C17H23N3O3 317.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21](OC)OC)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:28])[CH:3]=1.C(O)(C(F)(F)F)=O.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C([BH3-])#N.[Na+]>O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][NH:41][CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:28])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC(OC)OC
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCNC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (210 mg, 0.52 mmol), water (5 ml) and TFA (5 ml) was stirred at ambient temperature for 3 hours then heated at 60° C. for 1 hour. The solution was allowed to cool, then diluted with water and the resulting precipitate was collected by filtration and dried. The solid was dissolved in methanol (10 ml) and cyclopentylamine (0.057 ml, 0.57 mmol) and dried 3 Å molecular sieves (2.5 g) were added. The mixture was stirred for 30 minutes, glacial acetic acid (0.20 ml, 3.2 mmol) and sodium cyanoborohydride (150 mg, 2.4 mmol) were added and the reaction stirred for 4 hours then left to stand for 18 hours. The insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether/hexane, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-cyclopentylaminoethoxy)-6-methoxyquinazoline (80 mg, 36%).
Reaction SMILES: [CH:1]1[CH:19]=[CH:18][C:15]2=[C:16]3[C:17]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]=4[S:14]2)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=13.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:10]1[CH:11]=[CH:12][C:13]2[S:14][C:15]3[CH:18]=[CH:19][CH:1]=[C:2]4[C:16]=3[C:17]=2[C:9]=1[C:8]1[C:3]4=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)c1cccc3sc4cccc2c4c31
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1ccc2sc3cccc4c5ccccc5c1c2c34
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triphenyleno[1,12-bcd]thiophene (1.5 g, 5.8 mmol) was dissolved in 100 mL of chloroform. Br2 was slowly added into the reaction solution. After the reaction was stirred at room temperature for 3 days, the mixture was filtered through a Celite plug and washed by CH2Cl2. The combined filtrate was concentrated to get 2.2 g of 7-bromotriphenyleno[1,12-bcd]thiophene which was used for next step without further purification.
Reaction SMILES: S[C@:2]1([OH:33])[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:23])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:22])[CH2:17]CC(O)C)[CH2:3]1.C(O)(=O)C>CC(N(C)C)=O>[CH3:22][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:24]2([CH3:32])[C@H:8]([C@H:7]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:4]([CH2:3][C@H:2]([CH2:30][CH2:29]2)[OH:33])=[CH:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:23])[CH3:17]
Reactant: CC(O)CCC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(S)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -2 °C
Reaction time: 1 h
Yield: 325.8 %

Procedure:
The bromobutylated Tecothane (1.14 g, containing approximately 0.5 mmol of 4-bromobutyl groups) described above was dissolved in DMAc (20 ml) under argon and cooled to −2° C. A solution of 3-mercapto-2-hydroxypropyl-cholesterol (0.495 g, 1.04 mmol) in DMAc (8 ml) was added and a freshly prepared 0.12 M DMAc-solution of (Bu4N)2B4O7 (5 ml, 6 mmol) was also added. The mixture was stirred at −1 to 1° C. for one hour and acidified with acetic acid (0.12 ml, 2 mmol). The reaction solution was then filtered and the polymer was precipitated with methanol (150 ml). The precipitate was washed with methanol alternating with 2-propanol and stirred consequently with large amounts of 2-propanol, methanol, and water and dried under 0.05 mm Hg conditions. The procedure yielded 1.31 g of cholesterol-modified Tecothane. 1H NMR analysis of this polymer (DMF-d7) indicated covalent attachment of cholesterol to 20% of the urethane segments via noncleavable sulfide bonds (see FIG. 2) corresponding to approximately 0.4 mmol of pendant cholesterol moieties per gram of polymer.