Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([O:22]CC)=[CH2:21])[CH:14]=[CH:13]2>C1COCC1.O>[Br:8][CH2:22][C:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=1)=[O:21]
Reactant: C=C(OCC)c1ccc2cc(Br)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
NBS (407 mg, 2.287 mmol) was added to a solution of 6-bromo-2-(1-ethoxyvinyl)quinoline (530 mg, 1.91 mmol) in THF (10 mL) and water (2.5 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and brine and the organic layer was concentrated. The crude material was purified by flash silica gel chromatography (eluted with Et2O/hexanes, gradient from 0 to 5% Et2O) to yield 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (380 mg) as white solid. LC-MS retention time 3.988 min; m/z 329.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Cl>CN(C=O)C>[CH2:12]([O:19][C:9]1[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a mixture obtained by adding 5.0 g of 3,4,5-trifluorobenzonitrile and 4.5 g of benzyl alcohol to 25 ml of DMF was added 1.5 g of 60% sodium hydride (oily) at 0° C. The mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7.0 g of 4-benzyloxy-3,5-difluorobenzonitrile was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[NH:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:20]3[N:27]([C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:36]([O:35][CH3:34])[CH:37]=4)[CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cc[nH]c34)cc2Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)n2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1OC
Yield: 52.7 %

Procedure:
Under ice-cooling, to a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) and potassium carbonate (102 mg) in N,N-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl chloride (82 mg), and the mixture was stirred under ice-cooling, for 1 hr. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (104 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10]C)[C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[S:5][C:6]([CH2:9][Br:12])=[CH:7][CH:8]=1)=[O:10]
Reactant: COC(OC)c1ccc(C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)s1

Procedure:
To a mixture of 2-dimethoxymethyl-5-methylthiophene (3.44 g, 20 mmol) and N-bromosuccinimide (4.63 g, 26 mmol) in carbon tetrachloride (50 ml) was added a catalytic amount of benzoylperoxide. The mixture was refluxed for 1 hour. Undissolved materials were filtered off. The filtrate and the washings were combined and evaporated in vacuo to give 2-methoxycarbonyl-5-bromomethyl-thiophene as a yellow oil (4.65 g}, which was used in a following reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:52])=[N:44][CH:43]=1>>[NH2:52][C:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)=[CH:43][N:44]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Nc1ncc(Br)c2ccccc12
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)c4ccccc34)nc21

Procedure:
2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g) was reacted with 4-bromoisoquinolin-1-amine via General Procedure G to afford 115 following reverse phase purification. MS (Q1) 517.3 (M)+.—1H NMR (400 MHz, DMSO) δ 9.01 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.67 (t, 1H), 7.49 (t, 1H), 7.07 (s, 2H), 4.23 (s, 4H), 4.02 (s, 1H), 3.87-3.66 (m, 10H), 2.89 (d, 3H), 1.99 (t, 2H), 1.66 (d, 2H), 1.35-1.10 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[S:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[S:34]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: S=C=Nc1ccccc1Cl
Product: O=C1CC(=O)N(c2ccc(NC(=S)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 43.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190 mg, 0.60 mmol) obtained in Example 1, (3), and 2-chlorophenyl isothiocyanate (196 μL, 1.50 mmol), the title compound (127 mg, yield 44%) was obtained in the same manner as that of Example 20.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CCOCC>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol LIV (23.1 g, 0.175 mol) in pyridine (150 mL) at 0° C. was added tosyl chloride (44.5 g, 0.23 mol) in portions. The mixture was stirred for 7 h at 0° C. and was placed in a refrigerator for 18 h. Et2O (150 mL) was added and the mixture was washed with 1 N aqueous HCl (5×150 mL). The organic layer was washed with aqueous NaHCO3 (150 mL) and water (150 mL). The organic phase was dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude product was purified by column chromatography on silica gel (1:1 Et2O:hexane) to afford (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate LV (42.1 g, 0.15 mol, 84%).
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C@@H:3]1[O:8][C@H:7]([CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][C@@H:7]1[CH2:6][NH:5][CH2:4][C@H:3]([C@H:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:1])[O:8]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]([C@@H](O)c2ccccn2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H]([C@@H](O)c2ccccn2)O1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a stirred solution of (2R,6R)-tert-butyl 2-((S)-hydroxy(pyridin-2-yl)methyl)-6-methylmorpholine-4-carboxylate (150 mg, 0.486 mmol) in DCM (5 mL) was added TFA (1 mL) followed by stifling at rt for 1 h. The completed reaction was concentrated and azeotroped to dry three times with toluene (5 mL each) followed by diluting with DCM (10 ml) washing two times with saturated NaHCO3 in water (2 mL), brine (2 mL), drying over MgSO4, filtering and concentration and drying in vacuo to provide crude (S)-((2R,6R)-6-methylmorpholin-2-yl)(pyridin-2-yl)methanol (97.8 mg, 0.469, 96.4% yield).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34][CH:33]=1>>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:34][CH:33]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3c2CCCC3)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3CCCC4)cc2=O)nc1
Yield: 38 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 39) and 6-amino-nicotinic acid methyl ester afforded 6-{3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester as an off-white solid (153 mg, 38%); ES+-HRMS m/e calcd for C29H32N4O5 [M+H+] 517.2446 found 517.2442. 1H-NMR (300 MHz, CDCl3) δ ppm 1.06-1.31 (m, 2H), 1.31-1.99 (m, 1H), 2.11-2.42 (m, 2H), 2.55 (br s, 2H), 2.81 (br s, 2H), 3.93 (s, 3H), 5.64 (t, J=7.4 Hz, 1H), 5.93 (s, 1H), 6.83 (d, J=7.7 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.94 (s, 1H), 8.29 (s, 2H), 8.87 (s, 1H), 9.25 (br s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:26][C:27]1([CH3:61])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:61][C:27]1([CH3:26])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:28]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 6.6 g (17.2 mmol) of 9-bromo-10-(naphthalene-2-yl)anthracene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.9 g (yield 53%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 646.4; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.14 (s, 1H), 8.90 (d, J=7.80 Hz, 1H), 8.82 (d, J=7.92 Hz, 1H), 8.79 (s, 1H), 8.73 (d, J=7.88 Hz, 2H), 8.23 (d, J=7.72 Hz, 1H), 8.11 (d, J=8.24 Hz, 1H), 8.07˜8.02 (m, 2H), 7.96 (d, J=7.40 Hz, 1H), 7.89 (d, J=8.64 Hz, 2H), 7.78˜7.59 (m, 10H), 7.42˜7.33 (m, 4H), 7.20 (d, J=7.40 Hz, 1H), 1.76 (s, 6H).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[CH2:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N12CCCCC1C=NCCC2>>[C:17]([C:10](=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:18]
Reactant: N#CCc1ccccc1
Reactant: COC1=NCCCCC1
Agent: C1=NCCCN2CCCCC12
Product: N#CC(=C1CCCCCN1)c1ccccc1
Yield: 41.7 %

Procedure:
Stir 8.1 g of caprolactim methyl ether and 5.0 g of benzyl cyanide with 0.6 g of 1,5-diazabicyclo [5.4.0]undec-5-ene under nitrogen for 48 hours at 130°; distil off any excess benzyl cyanide under a high vacuum, and rub down the thus-produced residue with a little methyl alcohol before filtering to obtain 3.78 g of the title compound. Recrystallize from methyl alcohol to obtain a purer product, MP 108° to 113°.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]1COCC1.[Li]C.[NH4+].[Cl-]>C(#N)C.O>[CH2:1]([C@@:8]12[CH2:21][C@:20]([OH:22])([CH3:40])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)[C@](C)(O)C[C@@]21Cc1ccccc1
Temperature: -17 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a flame dried 50 mL round bottom flask was added the (4bR,7R,8aR)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide (0.28 g, 0.54 mmol) in a THF (5 mL). The solution was cooled to −17° C. in an ice/acetone bath. To the reaction was added MeLi*LiBr (0.1 mL). After 1 hour the LCMS indicated that starting material remained so an additional 0.15 mL was added. The reaction stirred to room temperature over 2 hours. By HPLC, 2.5% of the starting material remained. To the reaction was added NH4Cl slowly and off gassing was observed. The reaction was diluted to 125 mL with acetonitrile and water. The reaction was purified by reverse phase chromatography then was lyophilized. The resulting dried powder was dissolved in acetonitrile and water again with two drops of concentrated HCl. The solution was lyophilized to dryness. This afforded the title product (231.4 mg) as the HCl salt in 73% yield. LRMS ES+ 533.1 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.23-1.28 (m, 3H) 1.53-1.62 (m, 1H) 1.90-2.20 (m, 3H) 2.70-2.74 (m, 3H) J=8.26 Hz, 2H) 6.84-6.92 (m, 2H) 6.99-7.10 (m, 3H) 7.13-7.29 (m, 3H) 7.45 (dd, J=8.15, 1.91 Hz, 1 H) 7.56-7.65 (m, 2H) 7.77 (d, J=1.81 Hz, 1H) 7.88 (dd, J=8.26, 5.84 Hz, 1H) 8.51-8.63 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([NH2:13])=O)=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.S(Cl)(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]#[N:13])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc(C#N)c(Cl)nc1Cl
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) and DMF (15 mL), thionyl chloride (1 mL) was added at room temperature and stirred for 20 minutes. The reaction liquid was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane) to give 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg) as a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromothiophene-2-carbaldehyde 63 (Avocado, UK) (1.20 g, 6.3 mmol) in THF (50 mL) at rt was added dropwise morpholine (0.96 g, 11 mmol). After the reaction was stirred at rt for 5 minutes, NaBH(OAc)3 (3.18 g, 15 mmol) was added in one portion. The resulting mixture was stirred at rt for 3 h. Ethyl acetate (80 mL) was added and then washed with NaHCO3 (20 mL×2) and brine (20 mL). The organic layer was dried with MgSO4. After the solvent was evaporated, the residue was purified by silica gel column chromatography to give 64 (1.31 g). 1H NMR (400 MHz, CDCl3) 6, 2.50–2.52(m, 4H), 2.67 (s, 2H), 3.72–3.75 (m, 4H), 6.87(s, 1H), 7.15 (d, J=1.4 Hz, 1H). MS (EI) m/z (M+H+) 263.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][C:21]3[CH:22]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[N:24]([CH3:26])[CH:25]=3)=[O:19])[N:15]([CH3:17])[CH:16]=2)=[O:10])[N:6]([CH3:8])[CH:7]=1.[CH:35](N)=[O:36].C(OCC)=O>O>[CH:35]([NH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][C:21]3[CH:22]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[N:24]([CH3:26])[CH:25]=3)=[O:19])[N:15]([CH3:17])[CH:16]=2)=[O:10])[N:6]([CH3:8])[CH:7]=1)=[O:36]
Reactant: NC=O
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(N)cn3C)cn2C)cc1C(=O)NCCC(=O)O
Agent: Cl
Solvent: CCOC=O
Solvent: O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC(=O)O
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of the compound obtained in example 1 (4 g), formamide (12 ml) and ethyl formate (12 ml) was stirred at 90° C. for 5 hours. The organic solvent was allowed under vacuum, the brown residue treated with water (100 ml) and the suspension stirred for one hour. The suspension was filtered and the solid washed with cold water (20 ml) yielding, after desiccation under vacuum at 40° C., the title compound (6.8 g; y=90%) as a brown powder.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:1]=[O:3])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=S(=O)(CC(CCc1cncc(Cl)c1)NO)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To formic acid (400 μl, 10.8 mmol) at 0° C. was added acetic anhydride (102 μl, 1.1 mmol) and the mixture was then stirred at RT for 15 minutes. The mixture was then re-cooled to 0° C., and a solution of 1-(4-chlorophenyl)-4-{[4-(5-chloropyridin-3-yl)-2-(hydroxyamino)butyl]sulfonyl}piperazine (100 mg, 0.22 mmol) in THF was added dropwise via syringe. After stirring at RT for 1.5 hours, volatiles were removed in vacuo, and the residue was azeotroped with toluene (2 mL). The residue was then dissolved in methanol (5 mL) and stirred at 40° C. for 1 hour. After cooling to RT, the solvent was evaporated, and the residue dissolved in methanol (0.5 mL). Diethyl ether (5 mL) was then added and the cloudy suspension stirred at RT for 1 hour. The solid that precipitated was filtered, washed with diethyl ether and dried in vacuo, to give the title compound as an off-white solid (48 mg, 0.099 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].NC1N2C=CN=C2C(C([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:32][CH2:31]2)=O)=CC=1Cl>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:32][CH2:31]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NC3CCN(CCCOC)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2) and 1-[3-(methyloxy)propyl]-4-piperidinamine (EXAMPLE 3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1.[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][NH:24][CH3:25]>C(O)(C)C.O>[OH2:5].[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2ccncc2C1=O
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCC1CN(C)C(=O)c2cnccc2O1
Reaction time: 72 h

Procedure:
A solution of 5 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one, in 25 ml of dimethylamine was placed in a sealed vessel and stirred for 72 hr. The vessel was opened and the excess dimethylamine allowed to evaporate. The residue was dissolved in chloroform and the solvent was stripped off in vacuo to remove excess dimethylamine. The residue was partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and the residue was treated with 3 g (0.033 mole) of oxalic acid in 50 ml of isopropyl alcohol and enough water to dissolve the salt while boiling. The resulting crystals were recrystallized from the same solvent. Yield of product was 5.3 g (60%), m.p. 179°-181° C.