Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.C([O:11][C@H:12]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([O:26]CC2C=CC=CC=2)[C@@H:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([CH2:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14][CH:13]1[CH2:56][O:57]CC1C=CC=CC=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:57][CH2:56][C@@H:13]1[C@@H:12]([OH:11])[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([CH2:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14]1
Reactant: CCc1ccc2sc(Cc3cc([C@H]4OC(COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: CCc1ccc2sc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 31.6 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (2.66 ml) and a boron trifluoride-diethyl ether complex (1.03 ml, 8.12 mmol) were added to a solution of (3R,4R,5S,6R)-3,4,5-trisbenzyloxy-2-benzyloxymethyl-6-[3-(5-ethylbenzo[b]-thiophen-2-ylmethyl)naphthalen-1-yl]tetrahydropyran (670 mg, 0.81 mmol) in methylene chloride (4 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 1.5 days, and then a 50% methanol aqueous solution (20 ml) was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried with sodium sulfate, and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (50:1)] to obtain the title compound (119 mg, 32%).
Reaction SMILES: F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:46](=[O:48])[CH2:45][CH2:44][CH2:43][C:42]=3[N:41]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)[C:40](=[O:59])[N:39]2[CH2:60][C:61]([OH:63])=O)=[CH:34][CH:33]=1)#[N:31].[CH3:64][N:65]1[C:69]2[CH2:70][NH:71][CH2:72][C:68]=2[CH:67]=[N:66]1>CN(C)C=O>[CH3:64][N:65]1[C:69]2[CH2:70][N:71]([C:61](=[O:63])[CH2:60][N:39]3[CH:38]([C:35]4[CH:34]=[CH:33][C:32]([C:30]#[N:31])=[CH:37][CH:36]=4)[C:47]4[C:46](=[O:48])[CH2:45][CH2:44][CH2:43][C:42]=4[N:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:56])[F:58])[CH:50]=4)[C:40]3=[O:59])[CH2:72][C:68]=2[CH:67]=[N:66]1
Reactant: Cn1ncc2c1CNC2
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc2c1CN(C(=O)CN1C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C1c1ccc(C#N)cc1)C2

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (161 mg, 0.50 mmol) and triethylamine (210 μL, 1.51 mmol) are added to a mixture of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32, 235 mg, 0.50 mmol) in N,N-dimethylform-amide (2 mL). After 5 min a solution of 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (123 mg, 1.00 mmol) in N,N-dimethylformamide (3 mL) is added, and the mixture is stirred over night and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 86 mg; ESI mass spectrum [M+H]+=575; Retention time HPLC: 0.86 min (Z011_S03).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18]Cl.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([N:14]1[CH2:18][CH2:17][CH2:16]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: c1ccc(C(c2ccccc2)N2CCC2)cc1

Procedure:
Step 1, heating benzhydrylamine and 1-bromo-3-chloropropane in admixture with butanol, water and potassium carbonate to give N-benzhydrylazetidine and separating said N-benzhydrylazetidine therefrom;
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[C:19]([O:25][CH3:26])=[CH:18][C:17]=1[CH3:27])(=[O:3])[CH3:2].N(S([O-])(=O)=O)(S([O-])(=O)=[O:31])[O].[K+].[K+].O.P([O-])(O)(O)=O.[K+]>CN(C)C=O.CO>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:31])[C:17]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(CCCCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 672 h
Yield: 77.2 %

Procedure:
To a solution (400 ml) of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (8 g) in dimethylformamide are added potassium nitrosodisulfonate (24 g), water (400 ml), methanol (30 ml) and potassium dihydrogen phosphate (1.0 g), and the mixture is stirred at room temperature for 28 days. The product is extracted with dichloromethane and the dichloromethane layer is washed with water and then dried over anhydrous magnesium sulfate. Removal of the solvent by distillation gives crude crystals. Recrystallization from hexane yields orange-yellow needles of 6.4 g of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone. m.p. 41° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:5]=1C=O)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[K+].CO>C(Cl)(Cl)Cl>[OH:26][C:5]1[C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Yield: 71.4 %

Procedure:
A mixture of 2-nitro-4,5,6-trimethoxybenzaldehyde (19.3 g, 0.08 mol) and m-chloroperbenzoic acid (20.7 g, 0.12 mol) in chloroform (350 ml) was heated under reflux for 5 hours. After cooling, the reaction mixture was washed with 10% sodium bicarbonate solution and water. The solvent was removed by evaporation in vacuo and the residue was then treated with a mixture of 10% potassium hydroxide solution (potassium hydroxide 5.0 g, 0.088 mol in 50 ml of water) and methanol (150 ml) at room temperature under nitrogen. The solvent was removed in vacuo and the solid residue was dissolved in water (300 ml) and then acidified with 6N hydrochloric acid. The precipitated product was collected by filtration, washed well with water and dried to give (after recrystallization from 2-propanol) 13.1 g of 2-hydroxy-1-nitro-3,4,5-trimethoxybenzene, mp 72-73° C. 1H-NMR (CDCl3): δ3.87, 3.94, and 4.08 (each 3H, s, 3 ×OMe), 7.32 (1H, s, H-6), 10.78 (1H, exchangeable, OH). Analyses: Calculated for C9H11NO6 : C, 47.16; H, 4.84; N, 6.11. Found: C, 47.11; H, 5.00; N, 6.17.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C(COC)[O:15]C>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:15])=[CH:4][CH:5]=1
Reactant: COCCOC
Reactant: C[Si](C)(C)c1ccc(C(Br)Br)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: C[Si](C)(C)c1ccc(C=O)cc1
Yield: 99 %

Procedure:
The product of Step A (10 g, 30 mmole) was dissolved in dimethoxyethane (160 mL) and heated to reflux. A solution of silver nitrate (15.3 g, 90 mmole) in water (120 mL) was added dropwise while maintaining reflux. The reaction mixture was heated for 30 additional minutes and then cooled and the liquid decanted away from the percipitate. The solid was triturated with ether and the combined organic phases were washed once with water, dried (MgSO4), and concentrated to give the desired product as a pale yellow oil (6 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: ClCc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2cnccn2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 50 °C
Yield: 74 %

Procedure:
To a solution of 8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (0.62 g, 2.21 mmol), prepared as described in Example 354, in DMF (10 mL) at RT was added K2CO3 (0.61 g, 4.4 mmol) and 2-(chloromethyl)pyrazine (0.83 g). The reaction mixture was heated at 50° C. for 2 h. After this time, the mixture was diluted with EtOAc (150 mL). The resultant solution was washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes:EtOAc 1:2 to afford 0.61 g of the title compound, 8-chloro-7-(4-chlorophenyl)-2-(pyrazin-2-ylmethyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one as a yellow solid. HPLC RT: 2.86 min; MS, M+H=373; 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.54 (m, 2H), 8.11 (s, 1H), 7.54-7.49 (m, 4H), 5.48 (s, 2H).
Reaction SMILES: [CH3:1][C@@:2]1([OH:14])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[C:3]1([CH3:13])[CH3:12].[C:15](Cl)(=[O:17])[CH3:16]>>[CH3:1][C@@:2]1([O:14][C:15](=[O:17])[CH3:16])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[C:3]1([CH3:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CCC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Product: CCC=CC[C@@H]1CC[C@@](C)(OC(C)=O)C1(C)C

Procedure:
Using the procedure of Example 15, 2 g of (1R,S) 1,2,2-trimethyl-3-(2-pentenyl)-cyclopentanol and 10 ml of acetyl chloride were reacted to obtain 1.5 g of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(2-pentenyl)-cyclopentane.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([Sn](=O)CCCC)[CH2:19][CH2:20]C.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.ICCC>>[CH2:18]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:19][CH3:20]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCC[Sn](=O)CCCC
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Solvent: CCCI
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (10 g) was treated with dibutyl tin oxide (10.2 g, 1 eq). The resulting 2',3'-O-dibutylstannylene uridine was treated with iodopropane (8 ml, 2 eq.) at 110° C. as per Example 50 to give a mixture of the 2' and 3' isomers (5.5 g) as a foam.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C:24]([O:26][C@@H:27]([C@@H:63]([CH3:68])/[CH:64]=[CH:65]\[CH:66]=[CH2:67])[C@@H:28]([CH3:62])[C@H:29]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:30]([CH3:53])[C:31]([N:33]([CH2:35][C@H:36]([CH3:52])[C@@H:37]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:38]([CH3:43])/[CH:39]=[CH:40]\[CH2:41][OH:42])[CH3:34])=[O:32])=[O:25]>C(Cl)Cl>[NH2:23][C:24]([O:26][C@@H:27]([C@@H:63]([CH3:68])/[CH:64]=[CH:65]\[CH:66]=[CH2:67])[C@@H:28]([CH3:62])[C@H:29]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:56])[CH3:57])[C@@H:30]([CH3:53])[C:31]([N:33]([CH2:35][C@H:36]([CH3:52])[C@@H:37]([O:44][Si:45]([C:48]([CH3:51])([CH3:49])[CH3:50])([CH3:46])[CH3:47])[C@@H:38]([CH3:43])/[CH:39]=[CH:40]\[CH:41]=[O:42])[CH3:34])=[O:32])=[O:25]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N(C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of Dess-Martin periodinane (199 mg, 0.47 mmol) and CH2Cl2 (4 mL) at room temperature, is added a solution of (2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-[(2S,3S,4S,5Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-2,4-dimethyl-5-heptenyl]-N,2,4,6-tetramethyl-7,9-decadienamide (200 mg, 0.29 mmol) and CH2Cl2 (1 mL). After stirring at room temperature for 1 h, the mixture is quenched by adding saturated NaHCO3 (1 mL) followed by saturated Na2S2O3 (1 mL). This mixture is then stirred at room temperature for 30 min, and then extracted with CH2Cl2 (4×10 mL). The combined organic layers are then dried (Na2SO4), concentrated in vacuo, and then chromatographed (silica gel eluted with hexane/EtOAc 90/10) to give the desired compound (150 mg, 75.2%) as a colorless glassy solid.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:51][O:52][C:53]1[C:58](B(O)O)=[CH:57][CH:56]=[CH:55][N:54]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:33][C:17]=2[C:18]([C:58]2[C:53]([O:52][CH3:51])=[N:54][CH:55]=[CH:56][CH:57]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ncccc1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 120 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 μL)/ethanol (0.6 mL)/water (0.4 mL) was added K2CO3 (29 mg, 0.16 mmol), 2-methoxypyridine-3-boronic acid (20 mg, 0.128 mmol) and tetrakis-(triphenylphosphine)-palladium(0)(15 mg, 0.01 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 3 hours. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 46=0.6, Rf 288=0.1) and LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with EtOAc/Hexane (1/1) to afford pure 9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one (17), 18.0 mg, 48%.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:15][C:4]1[CH:3]=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Br)cc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)cc1C
Yield: 58.1 %

Procedure:
22.6 g of methyl 4-bromo-2-methyl-5-nitrobenzoate, 23 g of K2CO3 and 7.8 g of phenol were stirred at 120° C. for 2 hours in 300 ml of DMF. The solvent was removed in vacuo, 2 l of water were added, and the mixture was adjusted to pH=7 using aqueous HCl solution and extracted 3 times using 500 ml of EA each time. The organic phase was dried over Na2SO4, the solvent was removed in vacuo and chromatography on silica gel using EA/HEP 1:4 yielded 13 g of a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][C@@H:13]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH2:12][S:11]2)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:13]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH2:12][S:11]2)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2]
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)c(C(F)(F)F)c2)N1
Reactant: CC(C)CBr
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C#N)c(C(F)(F)F)c2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-3-(trifluoromethyl)aniline was converted to 4-cyano-3-(trifluoromethyl)phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[NH:13][C:12]2[CH2:22][O:23][C:24](=[O:25])[C:11]1=2)([O-])=O>O1CCCC1.[Ni]>[CH2:19]([O:18][C:16]([C:15]1[CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[C:11]2[C:24](=[O:25])[O:23][CH2:22][C:12]=2[NH:13][C:14]=1[CH3:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1N
Reaction time: 1.5 h
Yield: 56 %

Procedure:
58 mmol of ethyl 4-(2-nitrophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are dissolved in 200 ml of tetrahydrofuran, and 2 g of Raney nickel are added. Hydrogenation is carried out under a pressure of 50 bar of H2 for 1.5 h. The solution is evaporated, and dilute hydrochloric acid is added and the product is filtered off with suction and dried. Yield: 56% of theory
Reaction SMILES: Cl.CO[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8](N(CCC)CCC)[C@@H:9]2C.[BrH:22]>>[BrH:22].[CH2:9]1[C:10]2[C:5](=[CH:4][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CCCN(CCC)[C@H]1CCc2c(OC)cccc2[C@H]1C
Agent: Br
Agent: Cl
Product: c1ccc2c(c1)CCCC2

Procedure:
cis-5-Methoxy-1-methyl-2-(di-n-propylamino)tetralin hydrochloride (150 mg, 0.48 mmol) was heated in 48% aqueous HBr for 2 h at 120° C. under N2. The volatiles were evaporated in vacuo and the residue was applied to pre-coated PLC plates (silica gel 60 F254, Merck) which were eluted with CHCl3 -MeOH (9:1). After elution of the product the volatiles were evaporated in vacuo and the residue was recrystallized at least twice. giving cis-hydroxy-1-methyl-2-(di-n-propyl-amino)tetralin.Hbr (66 mg, 48%) of an isomeric purity >95% (GC, 225° C.) IR (KBr) ν3136 cm-1 (O-Hstr); NMR (MeOH-d4), δ1.05 (t,6H), δ1.31 (d,3H), δ1.50-3.74 (m,14H), δ6.44-6.69 (m,2H), δ6.81-7.07 (m,1H); MS (70 eV) m/z 261 (36%), 232 (100%), 161 (82%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (61 mg, 99%). LCMS calculated for C16H13ClF2NO (M−NH2)+: m/z=308.1. found: 308.0.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]3[NH:28][CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[O:1]([C:8]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]3[NH:28][CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (899 mg), 1N aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) was stirred at 60° C. for 1.5 hrs. To the reaction mixture was added 1N hydrochloric acid (5 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with water and acetone to give the title compound (768 mg) as a pale-brown powder.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[F:30])[C:3]([CH3:6])([CH3:5])[CH3:4].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:21][C:18]([Si:15]([O:14][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[F:30])=[C:7]([CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:16])[CH3:17])([CH3:19])[CH3:20]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(Cl)C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2CC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a stirred solution of 69.16B (0.015 g, 0.033 mmol) in toluene (2.00 mL) at 23° C. was added AIBN (0.00055 g, 0.0033 mmol) followed by tri-n-butyltin hydride (0.048 g, 0.17 mmol). The reaction was stirred at 100° C. for two hours. After which, the reaction was cooled to room temperature and concentrated in vacuo. The product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 69.16D as a colorless oil (0.013 g, 94% yield).