Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[C:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-])=O)(=[O:18])=[O:17])=[C:13]2[C:8]([C:9]([O:32][CH3:33])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1>CCO>[NH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=1[S:16]([NH:15][C:14]1[C:5]([Cl:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:32][CH3:33])(=[O:17])=[O:18]
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])c(Cl)ccc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)c(Cl)ccc12
Temperature: 95 °C
Yield: 86.2 %

Procedure:
Tin (II) chloride (2.0 g, 9.0 mmol) was added to a solution of N-(7-chloro-4-methoxy-quinolin-8-yl)-2-nitro-4-trifluoromethyl-benzenesulfonamide (Intermediate 194) (830 mg, 1.8 mmol)) in EtOH (20 ml) and the mixture was heated at 95° C. for 2 h. After cooling the solvent was removed in vacuo. EtOAc (100 ml) was added and the solution cooled in an ice bath whilst aqueous NH3 was added until the solution was basic, the white precipitate formed was filtered and washed with EtOAc (100 ml). The combined organics were washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (670 mg, 86%).
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:24])[NH:10][C:11](=[O:23])[N:12]([C@@H:14]3[O:22][CH2:21][C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:13]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>N1C=CC=CC=1.ClCCl>[C:31]([O:16][C@@H:15]1[C@H:17]([OH:18])[C@H:19]([OH:20])[CH2:21][O:22][C@H:14]1[N:12]1[CH:13]=[C:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:25])[C:3]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]3[C:1]2=[O:30])[C:9](=[O:24])[NH:10][C:11]1=[O:23])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 60597.3 %

Procedure:
10.6 g (0.025 mmol) of 5-(2-phtalimidoethyl)-1-(β-D-ribopyranosyl)uracil were dissolved in 20 ml of pyridine in a heated and argon-flushed 1 l four-necked flask and mixed with 200 ml of dichloromethane. The mixture was cooled to −70° C., 3.82 ml (0.033 mmol) of benzoyl chloride in 5 ml of pyridine and 20 ml of dichloromethane were slowly added dropwise with cooling and the mixture was stirred at −70° C. for 35 min. The reaction mixture was poured onto 600 ml of cooled ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried and concentrated to dryness in vacuo. Chromatography on silica gel (ethyl acetate/heptane 1:1) yielded 7.9 g (60%) of 1-(2′-O-benzoyl-β-D-ribopyranosyl)-5-(2-phtalimidoethyl)uracil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:38][CH2:39][C:34]([C:41]3[S:42][CH:43]=[CH:44][N:45]=3)([OH:33])[CH2:35][CH2:36]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3nccs3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (46.8 mg, 0.132 mmol) and 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (30.4 mg, 0.154 mmol) in dichloromethane (10 mL) was added triethylamine (23.6 uL, 0.169 mmol) followed by sodium triacetoxyborohydride (56 mg, 0.26 mmol) at room temperature. After being stirred overnight, the mixture was diluted with dichloromethane and neutralized with NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica to give two isomers. Isomer 1 and isomer 2: LC-MS calculated for C28H36F3N3O2S: (M+H)+536; found 536.2.
Reaction SMILES: [C:1]12([NH2:6])[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[C:7](Cl)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:1]12([NH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CC(=O)Cl
Reactant: NC12CC(C1)C2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)NC12CC(C1)C2

Procedure:
The commercially available bicyclo[1.1.1]pentan-1-amine can be coupled with an appropriate carboxylic acid or acid chloride, such as acetyl chloride in the presence of base (for example, K2CO3, Na2CO3, NaHCO3, TEA, pyridine, and the like) to give N-(bicyclo[1.1.1]pentan-1-yl)acetamide (4) (Scheme 3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][N:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:13]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:39](=[O:40])[CH2:38][CH2:37][C:15]1[C:16]([CH3:36])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][N:26]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[CH2:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C

Procedure:
[2-(3-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-ethyl]-carbamic acid tert-butyl ester is prepared in analogy to Example 37 by coupling (2-amino-ethyl)-carbamic acid tert-butyl ester with 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid; LC-MS: tR=1.14 min, [M+H]+=550.33.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:11]([CH3:18])([CH3:17])[C:12](OCC)=[O:13])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:11]([CH3:18])([CH3:17])[CH2:12][OH:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
1.9 g (50.2 mmole) of sodium borohydride were added to a solution of 1.75 g (5.2 mmole) of ethyl 3-(4-chlorophenyl)-2,2-dimethyl-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanoate in 25 ml of methanol, and then the mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was allowed to cool, and it was then poured into ice-water and extracted with ethyl acetate. The extract was washed with an aqueous solution of ammonium chloride, dried and concentrated by evaporation under reduced pressure, to afford 1.5 g (98%) of the title compound melting at 120°-135° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Br)[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Brc1cccc2cccc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc3cccc(-c4ccc(OC)cc4C)c23)c(C)c1
Yield: 99 %

Procedure:
A solution of 1,8-dibromonaphthalene, (1.29 g, 4.5 mmol), 2-methyl-4-methoxyphenylboronic acid, 3, (2.24 g, 13.5 mmol), Pd(PPh3)4 (0.78 g, 0.68 mmol) and K3PO4, (4.30 g, 20.0 mmol) in 50 mL toluene was stirred at 110° C. for 18 hours. The resulting mixture was allowed to come to room temperature, quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 2:3) afforded 1.66 g (4.5 mmol, >99%) of off-white crystals containing syn- and anti-isomers of 4.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (65.3 mg, 0.192 mmol), (2,5-dimethylphenyl)acetic acid (31.6 mg, 0.192 mmol), HATU (73.2 mg, 0.192 mmol) in DMF (2 mL) was added Hunig's base (0.134 mL, 0.770 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. It was filtered to give the product as a white solid. LC/MS (ES) m/z=413.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 2.25 (s, 3H), 3.24-3.31 (m, 2H), 3.84 (s, 2H), 3.94 (s, 3H), 4.28 (t, J=8.46 Hz, 2H), 6.99 (s, 2H), 7.08 (d, J=8.34 Hz, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.52 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]#[C:6][CH:7]([OH:17])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].N([O-])=O.[Na+]>O.[Pt]=O.C(O)C>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH:7]([OH:17])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: CCOC(C#CC(O)COCc1ccccc1)OCC
Agent: O=[Pt]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(CCC(O)COCc1ccccc1)OCC
Yield: 204 %

Procedure:
A solution of 5-benzyloxy-4-hydroxy-2-pentynal diethyl acetal (43.2 g) in abs. ethanol (250 ml) is hydrogenated in the presence of 82.7% platinum oxide (1.4 g), sodium nitrite (14 mg) and 1 drop of water for 90 minutes in a Parr hydrogenation apparatus. The reaction is repeated exactly as above with another (43.2 g) portion of 5-benzyloxy-4-hydroxy-2-pentynal diethyl acetal; the two mixtures are combined and the catalyst is removed by filtration through a bed of celite and washed with ethanol. The combined filtrate is evaporated in vacuo to give a residue (89.4 g, 100%). A 200 mg portion of the residue is purified on Quantagram PQ1F plates (developed in 40% CHCl3 /hexane three successive times). The principal band is eluted with ethyl acetate and the solvent is evaporated in vacuo to give 5-benzyloxy-4-hydroxypentanal diethyl acetate (152 mg); ir (neat) 2.88 μ (OH); nmr (CDCl3,δ): 1.17 (t, 6 H, OCH2CH3), 1.62 (m, 4H, CHCH2CH2CH), 2.7 (b, 1H, >CH-OH), 3.53 (m, 7H, OCH2CH3 and OCH2CH and ##STR6## 4.47 (m, 1H, >CHOH), 4.5 (s, 2H φCH2O), 7.28 (s, 5H, φCH2O).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:6]([O:13][C:14]([NH:16][C@H:17]([C:22](OCC)=[O:23])[C:18]([F:21])([F:20])[F:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[F:19][C:18]([F:20])([F:21])[CH:17]([NH:16][C:14](=[O:15])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:22][OH:23]
Reactant: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(F)(F)F
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(NC(CO)C(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of calcium chloride (2885 g, 26.23 mol) in diethyl ether (8 L) under a nitrogen atmosphere was added sodium borohydride (1993 g, 52.45 mol). To this mixture was added dropwise ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoroalaninate (3.28 M solution in diethyl ether, 2000 mL, 6.56 mol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 16 hours, reaction mixture was quenched with water (10 L) and extracted with ethyl acetate (3×2000 mL). The organic layers were combined, washed with brine (2×500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to afford benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.C(O)(C)C>C(=O)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: NC1=NC2(c3cccnc3)CN(c3ncc(F)cn3)CC2CS1
Agent: O=C=O
Solvent: CC(C)O
Product: NC1=N[C@@]2(c3cccnc3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 13.9 %

Procedure:
Racemic 6-(5-fluoropyrimidin-2-yl)-7a-(3-pyridyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (137 mg, 0.415 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralpak AD-H (5μ), 21.2×250 mm; eluent: 35% isopropanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The second eluting isomer is the title compound (19 mg). ES/MS (m/e): 331 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH2:11]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:11][CH3:10])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CN
Product: CNc1nc(N)nc(N)n1
Reaction time: 6 h
Yield: 65 %

Procedure:
A mixed solution comprising 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine synthesized in Reference Example 1 and 31.1 g (0.4 mol) of 40% aqueous solution of methylamine was heated under stirring and reacted finally at the reflux temperature thereof for 6 hours. After cooling the reacted solution, products were filtered off, and washed with cold water. The resulting filter residue was dried in vacuo at 70° C. for 6 hours to give 9.1 g (yield: 65%) of the titled compound. Malting point: 269° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C:16](=[O:17])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([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)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:54][Mg+].[Br-]>C1COCC1>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C@:16]([OH:17])([CH3:54])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:35])([CH3:34])[CH3:36])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@]1(NC(=O)N(C)C)[C@@H](NC(=O)OCc2ccccc2)[C@H]2O[C@@]2(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@]1(C)O
Temperature: 0 °C

Procedure:
A flame-dried 25-mL round-bottomed flask was charged with ketone 12 (1.7 g, 2.3 mmol, 1.0 equiv) and THF (23 mL). The solution was cooled to 0° C. and MeMgBr (3M in THF, 7.6 mL, 22.9 mmol, 10.0 equiv) was added dropwise. The reaction was stirred at 0° C. until TLC analysis indicated complete ketone consumption, typically 2 h. Saturated NH4Cl(aq.) (20 mL) was carefully added dropwise and the resulting mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (90:10 to 70:30 hexanes:EtOAc) to afford carbinol 13 as a clear, viscous oil with >10:1 diastereoselection (1.3 g, 75%). The enantiomeric ratio was assayed at this intermediate and was found to be 95:5. This composition was determined by SFC analysis (Chiralcel, OD, 4.0% MeOH, 1.5 mL/min, 150 bar, 210 urn; tR-minor 34.4 min, tR-major 37.6 min). Analytical data: [α]D19 +7.2 (c=0.70, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.2 Hz, 2H), 7.45-7.30 (m, 12H), 5.55 (br s, 1H), 5.21 (d, J=12.6 Hz, 1H), 5.17 (br s, 1H), 5.07 (d, J=12.0 Hz, 1H), 4.77 (br s, 1H), 4.64 (dd, J=8.4, 3.6 Hz, 1H), 4.21 (d, J=12.6 Hz, 1H), 4.12 (d, J=12.6 Hz, 1H), 3.90 (s, 1H), 2.75 (s, 6H), 1.30 (s, 3H), 1.25 (d, J=6.0 Hz, 3H), 1.07 (s, 9H), 0.97 (s, 9H), 0.11 (s, 3H), −0.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 158.8, 156.5, 136.3, 135.6, 135.5, 134.7, 133.3, 132.9, 129.6, 129.4, 128.4, 128.2, 128.1, 127.7, 127.6, 127.6, 67.1, 66.8, 62.1, 58.3, 36.1, 26.7, 26.5, 25.7, 23.8, 19.6, 19.2, 17.8, −4.2, −5.5; LRMS (ESI+) Calcd. for C42H61N3O7Si2+H, 776.41. Found, 776.36. IR (thin film, cm−1) 3430, 2429, 2359, 1716, 1635, 1506, 1456, 1112, 831, 700; TLC (90:10 hexanes/EtOAc): Rf=0.35.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:65])=[CH:53][CH:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH:56]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:55]2)[CH:17]([CH3:66])[CH:16]([O:67][Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])[CH2:15][C:14]1=[O:78])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:65])=[CH:53][CH:54]2[CH2:59][CH2:58][C:57](=[O:60])[CH:56]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:55]2)[CH:17]([CH3:66])[CH:16]([O:67][Si:68]([CH:72]([CH3:74])[CH3:73])([CH:69]([CH3:71])[CH3:70])[CH:75]([CH3:77])[CH3:76])[CH2:15][C:14]1=[O:78])[CH3:12]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride added dimethyl sulfoxide dropwise, followed by a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-14-triisopropylsiloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride. The reaction mixture is stirred for 30 min. at -78° C. and then triethylamine is added. The reaction mixture is allowed to rise to room temperature, poured into water, and extracted with ethyl acetate (three times). Combined organic layers are washed (water, sat'd NaHCO3), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography), gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:16]
Reactant: Cc1cc(Br)cc2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Br)cc2c(Cl)ccnc12
Yield: 95 %

Procedure:
A mixture of 6-bromo-8-methyl-4-quinolinol (1.42 g, 5.95 mmol) and phosphorous oxychloride (10.95 g, 71.40 mmol) was heated at reflux for 1 h, cooled, poured onto ice, and neutralized by addition of 30% ammonium hydroxide. The resulting solid was filtered and dried in a vacuum oven to give the title compound (1.45 g, 95%) as a tan solid. MS(ES)+ m/e 256 [M+H].