Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO>[CH2:18]([NH:9][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](COC(C)(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
Methyl O-tert-butyl-L-serinate hydrochloride (12 g, 56.7 mmol) was dissolved in methanol (120 ml), acetic acid (6.50 ml, 114 mmol), benzaldehyde (6.25 ml, 61.8 mmol), and sodium cyanoborohydride (1 M tetrahydrofuran solution, 75 ml) were added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated, diluted with water, and neutralized with sodium bicarbonate under ice cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the drying agent was removed by filtration and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [ethyl acetate:n-hexane=1:4 (v/v)] to give the title compound (7.75 g, 52%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH2:16][OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H](C=O)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-hydroxymethyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (2.31 g, 6.30 mmol, 1.0 eq.) was dissolved in CH2Cl2 (32 mL) and stirred at room temperature. Dess-Martin Periodinane (2.67 g, 6.30 mmol, 1.0 eq.) was added in one portion and the reaction is monitored by LC/MS and TLC. Upon completion, the reaction is diluted with EtOAc (200 mL) and extracted with 1M Na2S2O3 (100 mL), NaHCO3 (100 mL) and brine. The organic phase is dried over MgSO4, filtered and evaporated to provide 2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-formyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (1.41 g, 3.89 mmol, 62%) and used directly in the next step. HPLC-MS calcd. for C19H25FN2O4 (M+H+) 365.2, found 365.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.ClC1C=CC(C2NC3C=C(F)C(F)=CC=3N=2)=C([N+:56]([O-:58])=[O:57])C=1.BrCC1CCCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([N+:56]([O-:58])=[O:57])[CH:3]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Agent: BrCC1CCCCC1
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-Chloro-2-nitro-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Off-white powder (43%). MS (Turbo Spray): m/z=406.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[O-]S(C(F)(F)[F:49])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([F:49])=[C:19]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of 5 (170 mg, 0.25 mmol) in 3 mL CH2Cl2 was added 1-fluoropyridinium triflate (75 mg, 0.30 mmol), and then the mixture was stirred at room temperature until no 5 was detected by NMR. The resulting mixture was diluted with 40 mL Et2O, washed with brine (2×10 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/9:1) gave 6 (45 mg, 26%) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.78-7.63 (m, 6H), 7.56 (s, 1H), 7.50-7.41 (m, 5H), 4.25 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), and 1.50-1.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.88, 170.13, 168.24, 143.76, 142.84, 140.39, 135.53, 134.70, 133.95, 133.90, 132.08, 132.02, 131.85, 131.39, 129.70, 128.91, 128.87, 128.72, 128.21, 128.18, 127.32, 127.12, 123.20, 121.58, 120.91, 119.94, 119.78, 116.78, 116.76, 112.32, 52.30, 43.37, 36.95, 34.81, 27.06, and 25.51.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:17]2[O:18][C@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]1[C@H:17]2[O:18][C@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)[C@@H]2CC[C@H]1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of methyl (1R,2S,3R,4S)-3-{[(benzyloxy)carbonyl]amino}-7-oxabicyclo[2.2.1]heptane-2-carboxylate (2.23 g, 7.30 mmol) in ethyl acetate (60 mL), 5% palladium on carbon (0.5 g, 22% by weight) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h, passed through a plug of Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S,3R,4S)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.84 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.43 (2H, m), 1.67 (1H, m), 1.76 (1H, m), 2.82 (1H, d, J=7.6 Hz), 3.41 (1H, d, J=7.6 Hz), 3.73 (3H, s), 4.28 (1H, d, J=6.0 Hz), 4.81 (1H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:14]([O-:16])=[O:15])[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccc(F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 0 °C
Yield: 70 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Fluoro-1,4-dihydroquinoxaline-2,3-dione (200 mg, 1.10 mmol) was dissolved in 3 mL of concentrated H2SO4 and the blue green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (110 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice/H2O. The product was isolated by vacuum filtration as brown crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 173.4 mg (70.0% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:34]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Fe]>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:34])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2N)cc1
Yield: 90 %

Procedure:
The product from Example 172c was reacted with Fe and NH4Cl following the procedure of Example 9E to give the title compound (204 mg, 90%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:5][CH2:4]1.CO>[Ni].C1COCC1>[F:29][C:2]([F:1])([F:30])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:7][CH2:8]1
Reactant: Nc1cc(N2CCC(F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)cc1N
Reaction time: 1 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-(4-fluoro-piperidinyl)-4-amino-5-nitro-benzoic acid amide (150 mg, 0.35 mmol), Ra—Ni (15 mg), MeOH (2 mL) and THF (10 mL) is stirred under 50 psi H2-atmosphere for 1 h. The mixture is filtered and concentrated.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([CH2:37][CH2:38][C:39]#[N:40])[CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH2:37][CH2:38][C:39]#[N:40])[CH2:33][CH2:32]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCC[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a stirred suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.17 g) in propan-2-ol (32 mL), trans 3-(4-amino-cyclohexyl)-propionitrile trifluoroacetic acid salt (2.75 g, 10.3 mmol) and diisopropylethylamine (4.09 mL, 23.5 mmol) were added. The mixture was stirred at reflux for 16 hours and then cooled to 0° C. The suspension was filtered, and the solid washed with propan-2-ol (×2) and ether, then air dried to afford 3.83 g (90%) of trans 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile as a bright yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 8.99 (d, 1H), 8.19 (d, 2H), 7.66-7.59 (m, 2H), 7.52 (t, 2H), 6.67 (d, 1H), 3.91-3.80 (m, 1H), 2.40 (t, 2H), 2.24 (m, 2H), 1.96 (m, 2H), 1.66 (q, 2H), 1.55-1.39 m, 3H), 1.23-1.10 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[C@H:10]([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19]>ClCCl.C(OCC)C>[ClH:19].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:18])(=[O:15])=[O:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CNCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of (R)-4-methanesulfonyl-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (924 mg) in dichloromethane (20 mL) at 0° C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 2 h. The precipitate formed was then collected by filtration and dried to afford (R)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt as a white solid (520 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: N#Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Product: N#Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 84.5 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-cyanoindoline (0.50 g) obtained in Example 124 and active manganese dioxide (1.00 g) were treated as in Example 288 to give the title compound (0.42 g) as a white powder (yield: 83.8%).
Reaction SMILES: Cl[C:2]1C(Cl)=C(O)C(C#N)=C(C#N)[C:3]=1O.[F:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][NH:20]2>C1C=CC=CC=1>[CH2:2]([N:20]1[C:21]2[C:17](=[C:16]([F:15])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1)[CH3:3]
Reactant: O=[N+]([O-])c1ccc2c(c1F)CCN2
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Solvent: c1ccccc1
Product: CCn1ccc2c(F)c([N+](=O)[O-])ccc21
Yield: 70.4 %

Procedure:
2,3-Dichloro-5,6-dicyanohydroquinone (1.02 g, 4.50 mmol) was added to the solution of 4-fluoro-5-nitro-2,3-dihydro-indole (0.47 g, 2.25 mmol) in benzene (30 mL) and the mixture was refluxed for 7 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (3×10 mL), brine (3×10 mL), dried over anhydrous sodium sulphate and concentration in vacuo afforded the crude product. Purification by column chromatography over neutral alumina using 5% ethyl acetate in hexane as eluent afforded 1-ethyl-4-fluoro-5-nitro-indole (0.33 g, 72%) as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.O>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNn1cccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1cc(Cl)ncn1)n1cccc1
Temperature: 80 °C
Yield: 31.7 %

Procedure:
To a solution of 4,6-dichloropyrimidine (5.0 g), in 50 ml absolute ethanol was added triethylamine (5.8 ml), followed by a solution of N-methyl-1H-pyrrol-1-amine (3.2 g), in 30 ml ethanol. After stirring at 80° C. for twenty hours, the mixture was poured into 300 ml water, stirred for five minutes, and the resultant tan precipitate collected and dried to give 2.4 g, m.p. 88°-89° C. This material was sublimed at 75° C./1.0 mm Hg to give 2.2 g (31%) of 6-Chloro-N-methyl-N-(1H-pyrrol-1-yl)-4-pyrimidinamine, m.p. 88°-89° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH:8]=1)(=O)=O.C(N(CC)C(C)C)(C)C>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.CO>[N:13]1([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11][C:10]2([C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH2:9]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(OS(=O)(=O)C(F)(F)F)c3ccccc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 176.8 %

Procedure:
A mixture of the triflate (A2) (2.25 g, 5 mmol), methanol (10 ml), N,N-diisopropylethylamine (3 ml), tetrakis(triphenylphosphine)palladium(0) (340 mg), in DMF (20 ml) was degassed and exchanged with carbon monoxide. The mixture was stirred at 50° C. under 1 atmosphere of carbon monoxide for 20 h. After evaporation to remove the excess methanol, the mixture was poured into water, extracted with ether, and purified by flash chromatography to give 1′-tert-butyl 4-methyl 2H-spiro[naphthalene-1,4′-piperidine]-1′,4-dicarboxylate (B1) (1.58 g). LC-MS: m/e=302.0 (M+H—C(CH3)3). Rt=3.82 min. 1H-NMR (500 MHz, DMSO-d6): 7.67 (d, 1H), 7.41 (d, 1H), 7.30 (t, 1H), 7.24 (t, 1 H), 7.00 (t, 1 H), 3.82 (s, H), 3.78 (br. d, 2H), 2.75 (s, 3H), 3.29 (s, 3 H), 3.11 (br. s, 2H), 2.55 (s, 2H), 1.68 (m, 2 H), 1.61 (d, 2H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([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)[N:19]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:19]=2)[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a stirred solution of 3 g (5 mmol) ethyl 3,3-bis(4-fluorophenyl)-2-[2-triphenylmethyl-2H-tetrazol-5-yl]-2-propenoate in 50 mL of methylene chloride at -70° C., 10 mL (15 mmol) diisobutylaluminium hydride solution (1.5M in methylene chloride) was added and the solution stirred for 3 hours. The reaction was quenched with water and the mixture extracted with methylene chloride. The combined organic fractions were dried with magnesium sulfate and concentrated in vacuo to give 2.1 g of the title compound; m.p.=176°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20]C(O)=O)#[N:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[CH:20][C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
3,5-di tert.butyl-4-hydroxycinnamonitrile was prepared by heating a mixture of 85.5 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 62 grams of cyanoacetic acid, 360 milliliters of pyridine, and 18 milliliters of piperidine at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and poured into a mixture of 200 milliliters of concentrated hydrochloric acid and 350 grams of ice. The sticky solid tht precipitated was separated and recrystallized from petroleum ether. The yield was 48.8 grams of product which melted at 109° to 113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[O:16]=[C:17]([Cl:23])OC(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:17]([Cl:23])(=[O:16])[NH2:5].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Clc1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Product: NC(=O)Cl
Temperature: 140 °C

Procedure:
To a suspension of 2-chlorophenothiazine (2 g) in xylene (20 ml) was added diphosgene (3.4 g). The mixture was heated to 140° C. for 18 hrs. The mixture was then cooled and the xylene removed under reduced pressure. The residue was purified by flash chromatography (2-5% ethyl acetate/hexane) to afford the sub-title compound as a brown solid (2.04 g): 1H NMR (400 MHz, CDCl3) δ 7.26-7.43 (4H, m), 7.45-7.51 (1H, m), 7.59-7.68 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH2:21])[CH2:16]1.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:21][CH2:33][C:30]2[CH:31]=[CH:32][C:26]3[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=3[N:29]=2)[CH2:16]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(CCN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.22 g, 0.77 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24 h, at RT was added NaBH4 (0.03 g, 0.85 mmole). After 24 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.25 g, 70%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=4.5 Hz, 1H), 18.29 (d, J=9.1 Hz, 1H), 7.85 (m, 2H), 7.36 (d, J=9.1 Hz, 1H), 7.15 (d, J=5.8 Hz, 1H), 4.38 (s, 2H), 4.19 (s, 3H), 3.91 (m, 2H), 3.82 (m, 4H), 3.67 (s, 2H), 3.31 (m, 2H), 3.18 (m, 1H), 2.55 (m, 2H), 2.10 (m, 2H). LC-MS (ES) m/e 465 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([O:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3[nH]ccc23)C1
Yield: 92.8 %

Procedure:
To a solution of (S)-tert-butyl-3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.1 g, 0.22 mmol) in THF (5 mL) was added TBAF (291 mg, 1.1 mmol) and the reaction mixture was refluxed for 5 h. The reaction mixture was cooled and was concentrated in vacuo to give a residue which was partitioned between EtOAc (25 mL) and water (25 mL). The EtOAc layer was separated and the water layer was extracted with EtOAc (3×25 mL). The combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to give (65 mg, 74%) the titled compound.