Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([C:31]([OH:33])=O)[CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:31]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:23]=2[N:22]=[C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:16]=2)[CH:30]=[CH:29]3)=[O:33])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-c3ccc4cccc(C(=O)O)c4n3)c2)CC1
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1cccc2ccc(-c3cccc(OC4CCNCC4)c3)nc12

Procedure:
The same general amide coupling procedure outlined above was employed using 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)phenyl)quinoline-8-carboxylic acid and cyclopentylamine. Purification by column chromatography (1:5 ethyl acetate/pentane), followed by treatment with 4N HCl/MeOH and concentration produced the product as a yellow solid. MS (ESI) calcd for C26H29N3O2 (m/z): 415.23. found: 416 [M+1].
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH3:16]
Reactant: C[O-]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Agent: [Na+]
Solvent: CO
Product: CCc1ccc([N+](=O)[O-])cc1COC
Temperature: 3 °C

Procedure:
Sodium methoxide is added portionwise to a solution of 150.0 g of α-chloro-2-ethyl-5-nitrotoluene in 1.15 l. of methanol maintained between 18° C. and 30° C. The mixture is refluxed for 2 hours, cooled to 3° C., and filtered. The filtrate is concentrated under vacuum and the resulting slurry shaken with saturated aqueous sodium chloride and methylene chloride. The methylene chloride layer is washed, filtered through sodium sulfate, and stirred over magnesium sulfate. The filtered solution is concentrated under vacuum to yield 133.89 g. of a dark brown liquid. The crude product is fractionated by vacuum distillation to yield a yellow liquid with boiling point 113° C. to 115° C. at 0.35 mm Hg which solidifies to light yellow prisms with mp 21.5° C. to 23.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].CS(C)=[O:20].C(=O)([O-])[O-].[K+].[K+].OO>O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:20])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol), dimethylsulfoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3 mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature. Dilute with 100 mL of water, extract with ethyl acetate (3× 100 mL). Wash the organic phase with 100 mL of water, and 50 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via a Biotage Flash 40L system using 75:25 hexanes/ethyl acetate as eluting solvent to give 3.0 g (77%) of the title compound: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (br m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20](Cl)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)cnc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(-c4ccc(S(C)(=O)=O)cc4)cnc3o2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-(2-chloro-furo[2,3-b]pyrazin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg), 4-(methanesulfonyl)phenyl boronic acid (140 mg), Na2CO3 (126 mg), water (2.5 mL), and N,N-dimethylformamide (2.5 mL) is sparged with argon for 10 min and Pd(PPh3)4 (15 mg) is added. The resulting mixture is stirred at 100° C. for 1.5 h. After cooling to room temperature, water and ethyl acetate are added. The organic phase is washed with brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 60:40) to give an oily residue that is triturated with diethyl ether and dried to afford the title compound as a colorless solid. Yield: 175 mg (65% of theory); LC (method 2): tR=1.35 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[N:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH2:62].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH:62][C:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14]2[CH:13]=[N:12][C:11]3[N:10]([N:9]=[CH:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[N:21]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2cnc3c(-c4ccccc4)cnn3c2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc(-c2cnc3c(-c4ccccc4)cnn3c2)n1

Procedure:
A solution of 6-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)pyridine-2-carboxylic acid (6-1, 100 mg, 0.32 mmol, 1 equiv), benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (197 mg, 0.73 mmol, 1.2 equiv), N,N-dimethylethylenediamine (70 μL, 0.63 mmol, 2 equiv) and N,N-diisopropylethyl-amine (20 μL, 0.73 mmol, 2.3 equiv) in DMF (5 mL) was stirred at 23° C. for 3 hours. The solution was partitioned between EtOAc (3×100 mL) and water (120 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, then concentrated to afford N-[2-(dimethylamino)ethyl]-6-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)pyridine-2-carboxamide (6-2). 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1 H), 9.72 (s, 1 H), 9.42 (m, 1 H), 8.91 (s, 1 H), 8.47 (m, 1 H), 8.08 (m, 3 H), 7.48 (m, 2 H), 7.29 (m, 1 H), 3.73 (m, 2 H), 3.36 (m, 2 H), 2.89 (s, 3 H), 1.74 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccc(Cl)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)C(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 94.3 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (330 mg, 1.1 mmol), 2-chloro-3-methyl-6-(4-pyridyl)pyrimidin-4-one (246 mg, 1.1 mmol) and triethylamine (170 μl, 1.22 mmol) in tetrahydrofuran were refluxed. Usual workup and purification by silica gel column chromatography gave 2-(1-(tert-butoxy-carbonyl)-2-(4-chlorophenyl)-piperazine-4-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (500 mg, 93%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A solution of diketene (0.32 ml, 4.15 mmol) in toluene (2 ml) was added to an 80° C. solution of 4-bromo-2-nitroaniline (900 mg, 4.15 mmol) in toluene (7 ml) and the solution was heated at reflux for 5 h. Triethylamine (0.58 ml, 4.15 mmol) in toluene (2 ml) was added and refluxing was continued for 30 min. The cooled solution was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with 2:1 hexane/EtOAc to give the title compound as a yellow solid (920 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:38][C:39]([NH2:41])=[O:40])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (1 ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to stir for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by HPLC as described above to yield the title compound (0.005 g, 4.8% yield): ES-MS (m/z) 518 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:21]=2)(=[O:19])=[O:18])=[CH:15][N:16]=1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-({6-[(E)-2-(2,4-Difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (Step 1, 95 mg, 0.25 mmol) was suspended in methanol (1 mL) and acetic acid (70 μL). Morpholine (28 μL, 0.34 mmol) was added and the reaction stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride (15 mg, 0.25 mmol) was added and stirring continued for 2 days. 5N sodium hydroxide was added and the products extracted into dichloromethane, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (90% ethyl acetate/isohexane) gave the title compound as a yellow foam which was treated with ethereal HCl to give the hydrochloride salt (8 mg, 7%). δH (500 MHz, d6 DMSO): 11.24 (1H, s), 9.11 (1H, d, J=2.1 Hz), 8.38 (1H, dd, J=2.1, 8.2 Hz), 8.33 (1H, s), 8.08 (1H, d, J=7.8 Hz), 7.93 (2H, q, J=8.0 Hz), 7.87 (1H, d, J=16.1 Hz), 7.76-7.70 (2H, m), 7.46 (1H, d, J=16.1 Hz), 7.37-7.31 (1H, m), 7.18 (1H, td, J=2.1, 8.4 Hz), 4.43 (2H, s), 3.91 (2H, d, J=11.8 Hz), 3.74 (2H, t, J=11.8 Hz), 3.20 (2H, d, J=11.6 Hz), 3.12-3.06 (2H, m); m/z (ES+) 457 [MH+].
Reaction SMILES: C(OC(=O)[N:6]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:9]=1)C=C.C(N(C(C)C)CC)(C)C>C(Cl)Cl.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>[C:31]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
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: ClCCl
Product: CC(C)(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamic acid allyl ester (Intermediate 120, 168 mg) was dissolved in methylene chloride (5 mL), followed by addition of diisopropylethylamine (0.11 mL), 1,3-dimthylbarbituric acid (78 mg) then Pd(PPh3)4 (50 mg). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and chromatographed on silica gel with methyl chloride:methanol (95:5) to afford 120 mg of product in 86% yield. LC-MS showed the product had the expected M+H+ of 411. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.3 (s, 9H).
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:33])[C:8]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(O)C>[CH2:27]([O:26][C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][C:8]=1[C:7]([OH:33])=[O:6])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1cc(C(=O)OCC)c(OCCCCCC)cc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1cc(C(=O)O)c(OCCCCCC)cc1C(=O)O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 8.91 g (135 mmol) 85% aqueous KOH solution and 20 ml water is added to 16.3 g (38.57 mmol) 2,5-dihexoxyterephthalic acid diethyl ester in 20 ml ethanol and the whole is stirred for 2 hours at 90° C. The crude product precipitated by the dropwise addition of 12.5 ml conc. HCl with ice-cooling is filtered off, washed neutral with water and recrystallized from ethanol.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mo:6]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mo+4:6].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: [Mo]
Agent: O=S(=O)([O-])[O-]
Product: [Mo+4]

Procedure:
Technical grade MoO3 was slurred in the leach solution so as to obtain a 2:1 weight ratio of leach to solids. Slurries were heated to 75°-85° C. and maintained at that temperature for two hours. The slurries were stirred vigorously during the digestion. The molybdenum oxide was separated from the leach solution by filtration. Percent of the molybdenum lost to the leach was determined. The molybdic oxide was then washed twice. Washing involved slurrying the oxide in 70°-80° C. water for 10 minutes and filtering to separate it from the wash. Percent of molybdenum lost to washes was determined. Efficiencies are tabulated in Table I. The better efficiency was obtained by the leach containing NH4NO3. The substitution of nitrate ion for sulfate ion is apparently responsible for the better efficiency. Presence of sulfate ion increases molybdenum solubility in acid solution by forming molybdenum sulfate complexes. When some of the sulfate ion is replaced with nitrate ion, molybdenum solubility decreases. Presence of additional nitrate ion increased oxidation of molybdenum IV to molybdenum VI, resulting in less molybdenum in the sludge after NH4OH digestion.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]2=[O:25].[H][H]>CO.[Pd]>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[O:8][C:9]3[C:4]([C:5](=[O:25])[C:6]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][CH:2]=[CH:11][CH:10]=3)[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Agent: [Pd]
Solvent: CO
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccccc12
Yield: 100 %

Procedure:
To a solution of Example 2 (0.1 g, 0.249 mmoles) in methanol (10 ml), palladium on carbon 20 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 4 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as brown solid (0.080 g, 87% yield).: 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.08(d, J=7.8 Hz, 1H), 7.90(t, J=7.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55(t, J=7.4 Hz, 1H), 7.49(m, 3H), 7.31(d, J=6.5 Hz, 2H), 3.72(br s,4H), 3.42(br s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[CH3:34][NH:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CCO>[CH3:34][N:35]([CH3:36])[CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:12]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[O:13])=[CH:15][N:16]=[C:17]2[CH:22]=1
Reactant: CNC
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN(C)C)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A solution of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (33 mg, 0.068 mmol) and dimethylamine (0.34 mL, 0.68 mmol) in 1.4 mL of a 1:1 MeOH/EtOH mixture was treated at ambient temperature with excess (10 equivalents) sodium triacetoxyborohydride. The reaction mixture was stirred overnight at ambient temperature. Another 10 equivalents of sodium triacetoxyborohydride were added, and stirring was continued for a few more hours. The reaction mixture was quenched with an equal volume of saturated, aqueous sodium bicarbonate, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography on silica, with an 8% MeOH-2% 7N NH3/MeOH/DCM mixture as eluent, to afford 6.6 mg of desired product. MS (ES+APCI) m/z=468 (M+H) detected.
Reaction SMILES: CS(NCCN[C@@:9]1(CCN)[CH2:18][C@@H:17]2[N:12]([CH2:13][CH2:14][C:15]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:16]=32)[CH2:11][CH2:10]1)(=O)=O.C(Cl)Cl.N1C=CC=[CH:33][CH:32]=1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:18]1[CH2:9][CH:10]=[CH:11][N:12]2[C:17]=1[C:16]1[O:23][C:21]3[CH:20]=[CH:19][CH:33]=[CH:32][C:22]=3[C:15]=1[CH:14]=[CH:13]2
Reactant: c1ccncc1
Reactant: COc1ccc2c(c1)CCN1CC[C@@](CCN)(NCCNS(C)(=O)=O)C[C@@H]21
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C1=CN2C=Cc3c(oc4ccccc34)C2=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.50 grams (11.35 mmol) of (2R,11bS) 2-(2-methanesulfonamidoethylamino)-2-(2-aminoethyl)-9-methoxy-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine and 600 milliliters of methylene chloride containing 6.02 milliliters (25.01 mmol) of dry pyridine was cooled to 0° C. and 6.02 milliliters (11.91 mmol) of a 1.98M solution of phosgene in toluene was added dropwise over two hours. The mixture was stirred overnight at room temperature, washed with saturated aqueous NaHCO3 and brine, dried, filtered and concentraed in vacuo. The residue was chromatographed on 80 grams of silica gel using 1:4 methanolethyl acetate as eluant to obtain 1 gram of (2R,11bS) 9-methoxy-1,3,4,5',6,6',7,11b-octahydro-3'-(2-methanesulfonamidoethyl)-spiro-benzo[a]quinolizine-2,4'-(1'H-pyrimidin-2'-(3'H)-one as the free base. The HCl salt was prepared from 2-propanol and concentrated HCl. The HCl salt has a melting point 170°-174° C. with decomposition. The specific rotation for the HCl salt was -32.2°, c=0.012 g/ml, methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])(O)[C:7]1=[O:26])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[OH:25])[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A mixture of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (0.90 g, 2.00 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluroacetic acid (0.94 mL, 12.2 mmol) was heated at 90° C. for two days. After cooling down to ambient temperature, the mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/3) to give the title compound (0.37 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.35-7.22 (m, 3H), 6.82-6.71 (m, 2H), 6.52 (t, 1H), 5.10 (s, 1H), 4.45 (s, 2H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z 426.4 (M+1), 428.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[C:42]([Cl:41])[CH:43]=4)[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(OCc4cccc(Cl)c4)c3)cc2Cl)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 34 (500 mg) in DMF (10 mL), potassium carbonate (500 mg) and m-chlorobenzyl bromide (0.16 mL) were added and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then poured into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (520 mg) as a colorless powder.