Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:2][CH2:3][CH3:4].[C:11]([NH2:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1([CH2:7][CH2:8][CH2:9][CH3:10])[NH:20][C:11](=[O:19])[C:12]2[CH:13]=[CH:15][CH:16]=[CH:17][C:18]=2[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)c1ccccc1O
Reactant: CCCCC(=O)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1(CCCC)NC(=O)c2ccccc2O1
Yield: 92.5 %

Procedure:
A mixture of 20 g of dibutylketone, 19.3 g of salicylamide and 2.7 g of p-toluenesulfonic acid monohydrate is added to 300 ml of toluene and the mixture is refluxed overnight by making use of a dehydrator of Dean Stark. After cooling, the reaction mixture is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=95:5) to obtain 34 g of 2,2-dibutyl-4-oxo-2,3-dihydro-4H-1,3-benzoxazine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](O)=[O:19].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C\C(O)=O.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C(NC1C=CC(O)=CC=1)=O.C(O)C(N)(CO)CO.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/CO.CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COP(OCC[N+](C)(C)C)([O-])=O)=O.C(S)[C@@H](O)[C@H](O)CS>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]\[C:16](\[CH3:21])=[CH:17]\[CH2:18][OH:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccc(O)cc2)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Product: CC1=C(/C=C/C(C)=C/C=C\C(C)=C\CO)C(C)(C)CCC1
Reaction time: 0.25 h

Procedure:
Effect of all-trans Retinoic acid (atRA), 13-cis-Retinoic acid (13cRA) and N-(4-hydroxyphenyl)retinamide (4-HPR) on IMH: To 1 mL of buffered suspension of RPE membranes (100 mM Tris pH 8.0, 76.7 μg of protein) was added 60 μM or 6 μM of atRA, 13cRA or 4-HPR and incubated at room temp. for 15 min. A control reaction mixture without any inhibitor was also incubated at room temperature for 15 min. At the end of the 15 min incubation, all-trans-retinol [11-12-3H2] (0.2 μM) was added to the reaction mixtures (100 mM Tris pH 8.0, 76.7 μg of RPE protein, 0.2% BSA 100 μM of DPPC, 1 mM of DTT and 0.2 μM all-trans-retinol [11-12-3H2]) and incubated at room temperature for 30 min. At the end of this 30 minutes of incubation, an aliquot of the reactions were quenched to verify the equal addition of all-trans-retinol [11,12-3H2] and the effect of these inhibitors on LRAT. After this the control reaction mixture was incubated with atRA (60 & 6 μM), 13cRA (60 & 6 μM) or 4-HPR (60 & 6 μM) for 15 min. Now all the reaction mixtures were incubated with 30 μM of apo-rCRALBP (100 mM Tris pH 8.0, 7.7 μg of RPE protein, 0.2% BSA 100 μm of DPPC, 1 mM of DTT 30 μM apo-rCRALBP and 0.2 μM all-trans-retinol [11-12-3H2]) at 37° C. for 30 minutes. At the end of this incubation period the 200 μL reaction mixture was quenched by the addition of 750 μL ice cold methanol after which 100 μL of 1M sodium chloride solution was added, and 500 μl hexane (containing butylated hydroxy toluene at 1 mg/mL) was added to effect extraction of the retinoids. The retinoids were analyzed as previously described (27). The amount of 11-cis-retinol formed was used as a measurement of IMH activity. All experiments were performed in triplicate and the average values of these measurements were used for analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[CH:16]([CH2:17][CH2:18][S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:15][CH2:14][CH2:13][N:12]2[CH:39]=1.[NH:40]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:41]([C:63](O)=[O:64])[CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[CH3:71][C:69]([CH3:72])([O:68][C:66]([NH:40][CH:41]([CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:63]([N:15]1[CH2:14][CH2:13][N:12]2[CH:39]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]2[CH:16]1[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:64])=[O:67])[CH3:70]
Reactant: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of the product from Step 13.g. (compound xxi, where R2, R3, R5, R6, and R7 are H, R4 is 2-methoxyphenyl, and n is 1) (1.30 g, 2.45 mmol), Boc-(L)-Cys(Trt)-OH (1.14 g, 2.45 mmol), NMM (270 uL, 2.45 mmol), and HOAt (333 mg, 2.45 mmol) in THF (20 ml) was treated with EDC (470 mg, 2.45 mmol) at room temperature under N2. The reaction was stirred overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (25 ml) was added and the product was extracted with a 3:2 mixture of hexanes:EtOAc. The extracts were applied to a silica gel column and the product was eluted with 3:2/hexanes:EtOAc. Product fractions were combined and concentrated under reduced pressure to obtain a white foam (2.31 g, 97%) which was used without further purification. Mass spec. 977.6 MH+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[ClH:26]>O>[ClH:26].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Agent: Cl
Solvent: O
Product: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1

Procedure:
A solution of 13.7 mg (0.03 mmol) of the compound from example 1h in 0.5 ml of water and 0.5 ml of 37% strength hydrochloric acid was treated in a microwave at 180° C. for 5 min. It was then evaporated to dryness under reduced pressure, the residue was taken up in a little water, and the solution was freeze-dried. This resulted in 8.0 mg of the title compound as bishydrochloride in the form of an amorphous solid.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[C:2]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Temperature: 68 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a solution of (S)-tert-butyl 4-(1-amino-3-(4′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (produced in step (ii), 35 g) in DMF (2.5 rel. vol.) at room temperature was added diisopropylethylamine (4 mol. eq.) and T3P in DMF (50% wt/wt in DMF, 3 mol. eq.) under nitrogen. The resulting mixture was heated to 68° C. for 2 h. The reaction mixture was cooled to room temperature and quenched by dropwise addition of water (3 rel. vol.). The reaction mixture was stirred for 30 min and 2-methyltetrahydrofuran (15 rel. vol.) was added. The organic layer was washed with water (2×5 rel. vol.) followed is by saturated aqueous sodium hydrogen carbonate solution. The separated organic layer was concentrated to 10 rel. vol. under reduced pressure and then heated to 55° C. after which n-heptane (5 rel. vol.) was slowly added over a period of 15 min. The mixture was stirred for 30 min at 55° C. and then filtered, washed with n-heptane (2 rel. vol.) and dried at 50° C. to afford the sub-titled compound (26.2 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH:18]=[O:19])[C:6]([NH:8][C:9]1[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=1)=[O:7])[CH2:2][CH:3]=[CH2:4].Cl>O>[CH3:15][O:14][C:11]1[S:10][C:9]([N:8]2[CH:18]([OH:19])[CH2:17][CH2:16][N:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[C:6]2=[O:7])=[N:13][N:12]=1
Reactant: C=CCCN(CCC=O)C(=O)Nc1nnc(OC)s1
Agent: Cl
Solvent: O
Product: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O

Procedure:
The diethyl acetal of 3-[1-but-3-enyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>C(O)C>[CH2:1]([N:9]=[N+:10]=[N-:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccccc1
Yield: 139.4 %

Procedure:
The reaction of this crude benzyl bromide (6.56 g) and sodium azide (1.92 g) in ethanol (90 ml) as in Example 33 gave 5.48 g of crude benzyl azide. Chromatography on silica gel yielded 3.29 g of pure 3-(trichlorovinyl)benzyl azide.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=2[C:17](O)=[O:18])=[CH:10][CH:9]=1>C(OCC)C.C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=2[CH2:17][OH:18])=[CH:12][CH:13]=1
Reactant: O=C(O)c1c(F)cccc1Sc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1c(F)cccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiAlH4 (0.77 g, 20.4 mmol) is suspended in 30 ml of dry diethyl ether with cooling in an ice bath. 2-(4--fluorophenylthio)-6-fluorobenzoic acid (4.53 g, 17.0 mmol) in 6 ml of diethyl ether and 6 ml of THF is then added and the reaction mixture stirred at room temperature overnight. The reaction mixture is quenched sequentially with 0.8 ml of water, 0.8 ml of 15% NaOH aqueous solution, and 2.4 ml of water. The resulting white precipitate is filtered off and washed thoroughly with diethyl ether. The filtrate and washings are combined and concentrated to afford the subtitle compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[OH:15])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[O:15][CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3ccc(NC(=O)OC(C)(C)C)cc3c(=O)c2O)cn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2oc3ccc(NC(=O)OC(C)(C)C)cc3c(=O)c2OCc2ccccc2)cn1
Yield: 74 %

Procedure:
Prepared analogously to Example 5d), starting from 2-(6-methoxypyridin-3-yl)-3-hydroxy-6-(N-tertbutoxycarbonylamino)-4H-1-benzopyran-4-one. Yield: 74%; TLC (9/1 Chloroform/Methanol): Rf 0.89, 1H-NMR (d6-DMSO): 9.78 (s broad, 1H), 8.81 (d, 1H), 8.31 (d, 1H), 8.25 (dd, 1H); 7.79 (dd, 1H); 7.68 (d, 1H); 7.30 (m, 5H), 6.97 (d, 1H); 5.16 (s, 2H), 3.94 (s, 3H), 1.52 (s, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[OH:20])=[CH:15][CH:14]=1
Reactant: O=Cc1ccncc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccncc1)c1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Under a dry nitrogen atmosphere, an appropriate amount of freshly cut magnesium chips was suspended in 150 mL of THF. To this was added about 5% of a solution of 22.5 grams (0.100 mole) of 4-bromobenzotrifluoride in 75 mL of THF. The reaction mixture was then warmed to about 30° C. to initiate the reaction. Once the reaction was proceeding, the remainder of the solution of 4-bromobenzotrifluoride was added during a one hour period, at a rate to maintain the reaction mixture temperature at about 34° C. to about 38° C. Upon completion of addition, the reaction mixture was stirred during a one hour period, as it cooled to ambient temperature. After this time a solution of 8.5 grams (0.075 mole) of 4-pyridinecarboxaldehyde in 75 mL of THF was added portion wise while maintaining the reaction mixture temperature below 30° C. Upon completion of addition the reaction mixture was stirred at ambient temperature for about 18 hours. With vigorous stirring the reaction mixture was then poured into 600 mL of aqueous 10% ammonium chloride. The mixture was extracted with two 300 mL portions of ethyl acetate. The combined extracts were washed with 250 mL of an aqueous solution saturated with sodium chloride, then dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 21.2 grams of the subject compound. The product was used without purification in the following reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:36]=1[F:44])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC([C@H]1C[C@@H]1C1C=CC(O[C@H]2C3C(=C(OC4C=CC(OCC5C=CC=CC=5)=CC=4)C=CC=3F)CC2)=CC=1)=O)C>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:38]4[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[C:36]([F:44])[CH:37]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Agent: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)c(F)c4)ccc(F)c32)cc1

Procedure:
The title compound is prepared from (1S,2S)-2-[4-((R)-7-fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 0.8 g, 2.2 mmol) and 4-benzyloxy-3-fluorophenylboronic acid (2.21 g, 9.0 mmol) in a manner analogous to that described for Intermediate 6 (Yield 0.8 g). LC (METHOD 6): tR=0.96 min; Mass spectrum (ES+): m/z=557 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:10]C(OC(C)(C)C)=O)[CH2:5][S:6][CH2:7][CH:8]=[CH2:9].[ClH:19]>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:10])[CH2:5][S:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: C=CCSC[C@H](N)C(=O)OC

Procedure:
Methyl ester 29 (3.20 g, 11.6 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (40 mL). The resultant solution was stirred at rt for 18 h before being concentrated in vacuo to yield a white solid, 2.46 g, 100%.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]1=O.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH:40]5[CH2:41][CH2:42][O:37][CH2:38][CH2:39]5)[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: O=C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol), tetrahydropyran-2-one (39 μL, 0.42 mmol), NEt3 (78 μL, 0.56 mmol) and 4 Å powdered molecular sieves (300 mg) in DCE (3 mL) was stirred for 2 h before the addition of sodium triacetoxyborohydride (119 mg, 0.56 mmol). The resulting mixture was allowed to stir at r.t for 20 h then diluted with DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%). The resulting residue was dissolved in DCM and treated with 4M HCl in dioxane. The resulting solid was triturated with Et2O and dried in vacuo affording 772 (124 mg, 72%). LCMS (method I): RT 2.52 min, [M+H]+ 547.2. 1H NMR (DMSO, 400 MHz): δ 9.36 (1 H, s), 8.18-8.14 (1 H, m), 7.80-7.79 (1 H, m), 7.50-7.48 (2 H, m), 4.28 (4 H, brd s), 4.10-3.90 (6 H, m), 3.78-3.77 (5 H, m), 3.43-3.39 (7 H, m), 3.25-3.10 (1 H, m), 2.30-1.65 (7 H, m), 1.44-1.38 (3 H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC[C@H]2COC(C)(C)O2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COC[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
The crude product of (S)-(+)-4-(4-methoxybenzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (4.1 g) was dissolved in methanol (10 mL). The solution was added with 1N hydrochloric acid and stirred at room temperature for one day. The solution was adjusted to pH 6 by addition of saturated sodium hydrogen carbonate, and extracted four times with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed and the residue was purified by silica gel column chromatography to obtain (R)-(+)-3-(4-methoxybenzyloxy)-1,2-propanediol (2.4 g, 69%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH3:15])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: COc1ccccc1CCN
Solvent: CO
Product: COc1ccccc1CCN=C(NC#N)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with chloroform methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from chloroform-diethyl ether to give the title compound (0.45 g, 1.6 mmol, yield: 61%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCC1CCNCC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.28 mmol) and diisopropylethylamine (49 mL, 0.28 mmol) in CH2Cl2 (2 mL) was added 2-fluorobenzenesulfonyl chloride (54 mg, 0.28 mmol) and the mixture was stirred at ambient temperature for 18 hr. To the resulting mixture was added trifluoroacetic acid (0.70 mL) and stirred at ambient temperature for 18 hr. The reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the organic layer was concentrated to give 2-fluoro-N-piperidin-4-ylmethyl-benzenesulfonamide as a pale yellow solid. To a solution of above solid (0.076 g, 0.28 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) in 2-propanol (3 mL) was added (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (0.044 g, 0.21 mmol) and the resulting mixture was stirred at 100° C. for 18 hr. The mixture was concentrated, and the residue was purified by column chromatography (silica gel, 5% MeOH in CH2Cl2) to give N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-fluoro-benzenesulfonamide as a pale yellow solid (0.024 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[F:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]([F:17])=[C:8]3[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1F
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1c2n(c3ccccc13)COc1ccc(Cl)nc1-2
Yield: 47.5 %

Procedure:
A solution of 6-chloro-2-(3-fluoro-1H-indol-2-yl)pyridin-3-ol (120 mg, 0.46 mmol) and Cs2CO3 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100° C. (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2-chloro-12-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (60 mg, yield: 47.6%). 1H-NMR (CDCl3, 400 MHz) δ 7.63 (d, J=8.0 Hz, 2H), 7.06˜7.28 (m, 4H), 5.76 (s, 2H). MS (M+H)+: 275/277.