Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([C:59]#[N:60])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([C:59]#[N:60])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C#N)n2)CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nc5ccccc5o4)c3)c(C#N)n2)CC1
Temperature: 120 °C
Yield: 86.7 %

Procedure:
Compound [1] was prepared using the following procedure: A mixture of tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (291 mg), tert-butyl 4-(4-bromo-3-cyanopyrazol-1-yl)piperidine-1-carboxylate (150 mg), tris(dibenzylideneacetone)dipalladium (19.33 mg), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (17.34 mg) and potassium phosphate (0.084 g) in a mixture of dioxane (5 ml) and water (150 μl) was degassed. The resulting suspension was stirred and heated to 120° C. for 3 hours under argon. After the mixture was cooled to room temperature the solvent was concentrated, ethyl acetate (80 ml) and water (20 ml) were added. The organic layer was washed with brine, dried over Magnesium sulphate, filtered and evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 20 to 75% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-cyano-pyrazol-1-yl]piperidine-1-carboxylate (251 mg) as pale pink foam. The N-tert-butoxycarbonyl groups on the resultant product were removed using the procedure described for example 61. The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.82 (dd, 1H), 1.87 (dd, 1H), 2.01-2.09 (m, 2H), 2.58-2.67 (m, 2H), 3.04-3.12 (m, 2H), 4.34-4.42 (m, 1H), 7.43-7.52 (m, 2H), 7.81 (dd, 1H), 7.87 (dd, 1H), 7.92 (bs, 2H), 8.58 (s, 2H), 8.51 (s, 1H); Mass spectrum: M+H+ 386.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]1[CH:14]([CH3:17])[CH2:15]Cl.C([O-])([O-])=O.[K+].[K+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOCC>COCCOCCOC.CCOC(C)=O.O>[CH2:24]([N:31]1[CH2:15][CH:14]([CH3:17])[N:4]2[C:5](=[O:13])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][CH:3]2[CH2:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(CCl)N1C(=O)c2ccccc2CC1CCl
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOCCOC
Product: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of 3-(chloromethyl)-2-(1-chloropropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (from Isomer B, 0.16 g, 0.58 mmol), K2CO3 (0.16 g, 1.2 mmol), and benzylamine (0.075 ml, 0.67 mmol) in diglyme (1.5 ml) was heated at reflux for 6 h. After cooling to room temperature the reaction was transferred to a separatory funnel with ether and water. Extraction with ether and washing the organic layer with water (4×) and brine, and drying over MgSO4 afforded 0.15 g of crude product after evaporation of the solvent. Flash chromatography (SiO2, hexanes to 60% EtOAc in hexanes) afforded pure product (93 mg, 52% yield). MS (ESI) 307 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=[O:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CO)ccn23)c1
Yield: 75.8 %

Procedure:
3′-(7-Formylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (140 mg, 0.43 mmol) was suspended in chloroform (4 ml) and methanol (7 ml), sodium borohydride (82 mg, 2.17 mmol) added portionwise over 5 min then the reaction was heated under reflux for 1.5 h. The mixture was evaporated to dryness, the residue diluted with water (40 ml) and extracted with chloroform (2×50 ml). The combined organics were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification was effected by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-5%). The solid obtained was triturated with diethyl ether which gave the title compound (106 mg, 75%) as a white powder. 1H NMR (400 MHz, MeOD) δH 4.70 (2H, d, J 1), 6.97 (1H, dd, J 7 and 2), 7.55-7.60 (2H, m), 7.61-7.65 (1H, m), 7.67-7.80 (5H, m), 7.84-7.88 (2H, m), 8.65 (1H, dd, J 7 and 1); m/z (ES+) 326 (M++H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([C:24]3[N:25]=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(Cl)nn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 26.8 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.450 g, 1.50 mmol), 1-(6-chloropyridazin-3-yl)piperidin-4-amine (0.487 g, 1.95 mmol) and TEA (0.456 g, 4.50 mmol) was dissolved in dry MeCN (15 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was evaporated and the residue was diluted with EtOAc (150 ml) and washed with water (500 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 60:40→50:50 mixture of heptane and EtOAc as eluant, to give the title compound (0.191 g, 27%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.50 (m, 2H), 7.47-7.43 (m, 3H), 7.15 (d, 1H), 6.81 (d, 1H), 5.20 (d, 1H), 4.11-4.05 (m, 2H), 3.22-3.13 (m, 1H), 2.60-2.52 (m, 2H), 1.80-1.73 (m, 2H), 1.72 (s, 9H), 1.41-1.32 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 158.6, 147, 133.8, 131.6, 130, 128.8, 128.7, 125, 115.4, 107.3, 61.6, 50, 43.8, 31.6, 27.6.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>C(N(CC)CC)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][P:28](=[O:35])([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCOCCOCCOCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCC
Temperature: 70 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of commercially available 2,4-dichloro-3-nitroquinoline (1 equiv.) in triethyl amine (0.30 M) was added commercially available diethyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)phosphonate (1.3 equiv.) (provided by PHARMARON). The resulting reaction mixture was stirred at 70° C. for 2 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (63%) as a solid.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[O:11]=[C:12]1[C:25]2[CH:24]=[CH:23][C:22]([C:26](O)=[O:27])=[CH:21][C:20]=2[S:19](=[O:30])(=[O:29])[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:11]=[C:12]1[C:25]2[CH:24]=[CH:23][C:22]([C:26]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:27])=[CH:21][C:20]=2[S:19](=[O:30])(=[O:29])[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2S(=O)(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.346 g (1.2 mmol) of 9-oxo-9H-thioxanthene-3-carboxylic acid 10,10-dioxide and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>C1COCC1.O=[Mn]=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(CO)cc2s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Nc1nc2ccc(C=O)cc2s1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of (2-aminobenzo[d]thiazol-6-yl)methanol (1.90 g, 10.5 mmol, 1.0 eq.) in THF (75 mL) under nitrogen was added MnO2 (14 g, 161 mmol, 15.3 eq.). After stirring overnight, the reaction solution was filtered through Celite and rinsed with THF. The filtrate was concentrated in vacuo to give 2-aminobenzo[d]thiazole-6-carbaldehyde as a yellow solid (1.64 g, 87% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1.C(O)C>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:21][NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:23][CH:22]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NN=Cc1ccnc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of 7.86 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 8.53 gm (0.05 mole) of 4-chlorobenzhydrazide, 400 ml of ethanol and 100 ml of tetrahydrofuran is refluxed 2 hr. Thin layer chromatography of the reaction mixture establishes that the reaction is complete. The reaction mixture is concentrated to one-half the original volume and then cooled to room temperature. The solid which separates is collected, washed with ethanol and dried to give 13.18 gm (85%) of title compound, having a melting point of 232.6° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@H:12]4[C:18](=O)[N:17](COCC[Si](C)(C)C)[C:16]5[CH:28]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]6[C:40]([O:84][CH3:85])=[CH:41][C:42]7[C:48](=[O:49])[N:47]8[CH:50]=[C:51](/[CH:53]=[CH:54]/[CH2:55][NH:56][C:57](=[O:73])[O:58][CH2:59][CH:60]9[C:72]%10[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=%10[C:66]%10[C:61]9=[CH:62][CH:63]=[CH:64][CH:65]=%10)[CH2:52][C@H:46]8[C:45](=O)[N:44](COCC[Si](C)(C)C)[C:43]=7[CH:83]=6)[C:30]([O:32][CH3:33])=[CH:31][C:15]=5[C:14](=[O:86])[N:13]4[CH:87]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[B-](CC)(CC)CC>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@H:12]4[CH:18]=[N:17][C:16]5[CH:28]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]6[C:40]([O:84][CH3:85])=[CH:41][C:42]7[C:48](=[O:49])[N:47]8[CH:50]=[C:51](/[CH:53]=[CH:54]/[CH2:55][NH:56][C:57](=[O:73])[O:58][CH2:59][CH:60]9[C:61]%10[CH:62]=[CH:63][CH:64]=[CH:65][C:66]=%10[C:67]%10[C:72]9=[CH:71][CH:70]=[CH:69][CH:68]=%10)[CH2:52][C@H:46]8[CH:45]=[N:44][C:43]=7[CH:83]=6)[C:30]([O:32][CH3:33])=[CH:31][C:15]=5[C:14](=[O:86])[N:13]4[CH:87]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Temperature: -78 °C
Reaction time: 120 h
Yield: 78.5 %

Procedure:
SEM dilactam 14d (0.223 g, 0.183 mmol, 1.0 eq.) was solubilised in THF (10 mL) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (0.373 mL, 0.373 mmol, 2.04 eq.). was added dropwise over 5 minutes. After 20 minutes an aliquot was washed with water for LCMS and TLC analysis and after 30 minutes water (30 mL) was added and the cold bath removed. The organic layer was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dissolved in MeOH (12 mL), DCM (6 mL) and water (2 mL) and enough silica gel to form a thick stirring suspension which was left for 5 days. The suspension was filtered and washed with DCM/MeOH 9:1 (˜200 mL) until complete elution of product. The organic layer was washed with brine (2×70 mL), dried over MgSO4, filtered and concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, 100/0 to 90/10 v/v CHCl3/MeOH) to afford the product as a yellow solid (0.133 g, 79%). LC/MS (2.916 min (ES+)), m/z: 926.33 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]Cl)([O-:22])=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[C:8]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])=[CH:7]1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: Nc1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Solvent: ClCCl
Product: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 1-(3,5-Difluoro-benzyl)-1H-indol-6-ylamine (25 mg, 0.1 mmol) in DCM (4 mL) was added 2-nitrobenzenesulfenyl chloride. The resulting yellow solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and purified over a SiO2 column (heptane/ethyl acetate 9:1) to give the title compound as an orange solid (11.6 mg, yield=28%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:39])=[C:12]([N:14]([CH2:25][C:26]([N:28]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)[CH3:29])=[O:27])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])=[O:17])[CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:39])=[C:12]([N:14]([CH2:25][C:26]([N:28]([N:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38]2)[CH3:29])=[O:27])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[CH3:24])=[O:17])[CH:13]=1)([OH:7])=[O:5]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)O)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.7 %

Procedure:
The compound (0.30 g, 0.56 mmol) obtained in step C was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1.36 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (methanol-dichloromethane) to give the title compound (0.32 g) as a colorless amorphous solid. This was directly used for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: COC(=O)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
A solution of (1R,2S)-methyl 2-((S)-3-(benzyloxy-carbonylamino)-2-oxopyrrolidin-1-yl)-5-oxocyclo-hexanecarboxylate (3.1 g, 8 mmol) in DMSO (7 ml) was treated with t-butylamine (1.75 g, 24 mol) and stirred for 10 minutes before Ti(i-OPr)4 (6.8 g, 24 mol) was added and the resulting mixture was stirred at room temperature for 2.5 h. Then NaBH4 (0.3 g, 8 mol) was added and stirred for 1.5 h before diluting slowly with methanol (gas evolution) and the resulting solution stirred an additional 1 h. While stirring vigorously, a sat'd solution of NaHCO3 was added, and the resulting suspension was filtered through Celite. The filter cake was washed thoroughly with CH2Cl2 several times and the combined washes were transferred to a separatory funnel. The organic layer was separated and washed with water and brine, concentrated and the residue chromatographed on silica gel (5% MeOH/CH2Cl2-8% NH4OH/MeOH/CH2Cl2) to give 3.0 g (80%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexane-carboxylate. MS found: (M+H)+=446.30. Also obtained was 400 mg of the isomeric (1R,2S,5S)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate. MS found: (M+H)+=446.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Li+].CC([N-]C(C)C)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>C1COCC1>[CH2:19]([CH:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2sccc21
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccsc2CCC1Cc1ccccc1
Temperature: -30 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (0.5 g, 3.3 mmol) in THF (7.5 mL) was added drop-wise to LDA (2.2 mL, 3.67 mmol) under a nitrogen atmosphere at −78° C. The mixture was warmed to −30° C. for 10 min before being re-cooled to −78° C. Benzyl bromide (1.17 mL, 9.9 mmol) was then added drop-wise and the mixture was gradually warmed to room temperature and stirred for 18 hr. Saturated ammonium chloride solution was added to the reaction mixture and product was extracted into ethyl acetate (×3). The combined organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution of 0-50% ethyl acetate in iso-hexane to afford the title compound as a yellow oil (0.55 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][CH3:16])[CH:7]=[C:6]2[OH:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22](OC2C3C(=CC(OC)=C(OC)C=3)N=C(N)C=2)=[C:21]([F:41])[CH:20]=1>>[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:17][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[C:8]([NH:15][CH3:16])[CH:7]=2)=[C:21]([F:41])[CH:20]=1
Reactant: CNc1cc(O)c2cc(OC)c(OC)cc2n1
Reactant: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC
Product: CNc1cc(Oc2ccc(N)cc2F)c2cc(OC)c(OC)cc2n1

Procedure:
[4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-amine was synthesized from 6,7-dimethoxy-2-methylamino-quinolin-4-ol in a similar manner as 4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine, and isolated as a yellow oil (58% yield). LCMS: m/z 330 (M+H)+.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1[NH2:26].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[F:21][C:19]1[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]2[N:15]([N:14]=[C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:26]=2)[CH:20]=1
Reactant: COC(=O)c1cc(N)[n+](N)cc1F
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 100 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
A mixture of 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate (1.719 g, 4.46 mmol) and benzoyl chloride (1.03 ml, 8.92 mmol) in pyridine (12 ml) is stirred for 20 hours at 100° C. The solvent is evaporated and the residue stirred for 2.5 hours with sat. aqueous ammoniumchloride solution while neutralizing to pH 6-7 with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording methyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (603 mg, 49.8%) as a light brown solid. Mp.: 162-8° C. MS: m/z=272.2 (M+H+).
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([C:20](O)=[O:21])[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:27])[C:15]2=[O:28])=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([CH2:20][OH:21])[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:27])[C:15]2=[O:28])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C(=O)O)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(CO)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Yield: 100 %

Procedure:
A BH3-THF solution (100 ml, 100 mmol) was added carefully to compound (10) (8.4 g, 23.88 mmol) in a 100 ml round-bottomed flask. The resulting solution was stirred at about r. t. overnight. MeOH was added. The solution was concentrated to dryness to give the title compound (8.15 g, 23.89 mmol, 100% yield) as a yellow solid. LC-MS (ESI+): m/e 338(M+H)+, Rt: 1.65 min.