Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9](=[O:16])[NH:8][C:7]1=[O:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>C1COCC1>[F:14][C:12]([F:13])([F:15])[C:10]1[C:9](=[O:16])[NH:8][C:7](=[O:17])[N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[CH:11]=1
Reactant: O=c1[nH]c(=O)n(CCCCO)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.7 %

Procedure:
1-(4-Hydroxy-butyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione (Prep 23, 44 mg, 0.17 mmol) was dissolved in dry THF (5 mL), the solution was cooled to 0° C. and Dess-Martin periodinane (127 mg, 0.28 mmol) was added. The mixture was stirred at 0° C. for 1.5 hours. Et2O was added and the solution washed with aqueous saturated NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to give 22 mg of the title compound (50% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH:17]([OH:19])[CH3:18].BrC(C)CO.C(N(CC)CC)C>C(#N)C>[OH:19][CH:17]([CH3:18])[CH2:16][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(Br)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol), 1-bromopropan-2-ol (2.8 g, 20.0 mmol, commercial product which also contained 30% of the regioisomer 2-bromopropan-1-ol), triethylamine (4.2 mL, 30.0 mmol), and acetonitrile (15 mL) were combined in a microwave vial and heated to 70° C. for 4 hours. The reaction mixture was concentrated to dryness. The crude product was partitioned between ethyl acetate/water. The aqueous phase was re-extracted 2× with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The product was purified by flash chromatography on silica gel eluting with a gradient of 20-30% methanol in dichloromethane to give 1.7 g of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2cc(F)cc(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cc(F)cc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3,5-difluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([OH:26])[CH3:25].OS([O-])(=O)=O.[K+]>O>[CH2:1]([NH:8][C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:26][CH2:24][CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product obtained at (655b) (15.5 g, 2.97 mmol) was combined with a mixture of potassium tert.-butylate (6.00 g, 53.5 mmol) and 400 mL ethanol, that was stirred at ambient temperature already for 15 min. After stirring for 1 h, 400 mL ethanol were added. After further 1 h of stirring, potassium tert.-butylate (500 mg, 4.46 mmol) was added. After further 1.5 h, the mixture was poured into water and acidified with KHSO4 (aq). After stirring for 20 min, the precipitate was filtered off, washed with water and dried at 55° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(C)c1=O
Reactant: NC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2cc(F)ccc21
Yield: 86.2 %

Procedure:
Cyclohexylamine (1.98 mL, 17.34 mmol) was added to a solution of Compound 41 (2.3 g, 8.67 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 2.38 g (97%) of white solids. M.P. 193° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 3.62 (s, 3H), 3.90 (m, 1H), 7.70 (m, 3H), 7.77 (d, J=8.0 Hz, 1H), 10.41 (s, 1H). EIMS m/z 341 (M+23).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCN1CCOCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCN5CCOCC5)n4)cc3)cc12

Procedure:
Using 3-(morpholin-4-yl)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:40][CH2:39][C:37]2[N:38]=[C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:35][C:36]=2[CH3:52])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.79-7.94 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 7.07 (d, 2H, J=8.4 Hz), 6.89 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.4 Hz), 4.19 (t, 2H, J=6.4 Hz), 3.24 and 3.14 (d of Abq, 2H, J=14.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 3.00 (bs, 1H), 2.39 (s, 3H), 1.42 (s, 3H). IR (KBr) 3600, 2980, 1725, 1611, 1504, 1265 cm−1. HRMS (ES+) m/z exact mass calcd for C29H27NO6F3 542.1790, found 542.1802.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:24]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1
Yield: 91 %

Procedure:
In substantially the same manner as in Example 5, morpholine (278 μl) was condensed with Boc-p-fluoro-L-phenylalanine (900 mg, manufactured by Bachera Fein Chemikalien AG, Switzerland) to give N-(Boc-p-fluoro-L-phenylalanyl)morpholine (1.02 g) as a white powder (yield 91%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (333 mg) to yield the title compound (compound 69; 520 mg) as a white powder (yield 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[N:39][CH:40]=2)O1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:40]=[N:39][C:38]([N:41]3[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.216 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (94 mg, 0.324 mmol). The product obtained from HPLC purification was treated with a saturated solution of NaHCO3, and solids that crashed out were filtered. The product was evaporated from MeOH, triturated from ether and then CH3CN. After drying in vacuum oven overnight, the final product was collected as a white solid (87 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.59-8.67 (m, 2H) 8.54 (s, 1H) 8.35 (s, 1H) 8.02-8.09 (m, 2H) 7.84 (s, 1H) 6.94 (d, J=9.09 Hz, 1H) 5.89 (s, 1H) 5.14 (dt, J=13.07, 6.47 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.41-3.47 (m, 4H) 3.17 (s, 1H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H). LC-MS (ES) m/z=500.4 [M+H]+ Note: some piperinzyl proton atoms hidden under water peak.
Reaction SMILES: [Mg].[CH3:2][Si:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(Cl)Cl.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.C=CC=C>CCOCC.C(O)(C)C>[CH3:2][Si:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: C1CCOC1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Agent: C=CC=C
Agent: [Mg]
Solvent: CC(C)O
Solvent: CCOCC
Product: C[Si]1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), methylphenyldichlorosilane (38.2 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Isopropyl alcohol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. The expected compound (boiling point 85°-87° C. at 4 mm Hg, 22.6 g, 65 % yield) was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available 2-chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCOC(C)=O>C1COCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2ccc(NC=C3C(=O)Nc4ccccc43)cc2)CC1
Temperature: 50 °C

Procedure:
A solution of 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (66 mg, 0.157 mmol) in 1 mL THF is treated with 1-methylpiperazine (37.2 μL, 2.2 equiv.) and the resulting reaction mixture is heated at 50° C. for 4 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between EtOAc and H2O. The organic layer is collected and washed with saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. The yellow solid residue obtained upon evaporation is broken up in 1:9 EtOAc:hexane and collected by filtration to give the named compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH2:15]2)=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:22])=[O:21].[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[CH3:23][O:21][C:20](=[O:22])[CH2:19][NH:18][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:14][CH2:13]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1cc2c(cc1OCc1ccccc1)CCC2
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CNc1cc2c(cc1OCc1ccccc1)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-benzyloxyindan-5-ylamine (2.00 g, 8.37 mmol) in MeCN (50 mL) is added AcOH (25 mL) followed by ethyl gloxylate (50% in toluene, 2.49 mL, 12.6 mmol). This is stirred for 2 h, then cooled to 0° C. A slurry of sodium triacetoxyborohydride (3.55 g, 16.7 mmol) is added and this is stirred for 10 min, at which time LCMS reveals complete consumption of the starting material. The reaction is diluted with saturated NaHCO3 and DCM, and the organic layer is separated, washed with brine, dried over MgSO4 and concentrated in vacuo to afford (6-benzyloxyindan-5-ylamino)-acetic acid methyl ester as a brown gummy solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:14]([Br:15])=[CH:13][S:12][N:11]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:14]([Br:15])=[CH:13][S:12][N:11]=1)=[N:2][CH3:1])#[N:16]
Reactant: CNC(=S)NCCSCc1nscc1Br
Reactant: N#CN
Agent: [Pb]
Product: CN=C(NC#N)NCCSCc1nscc1Br

Procedure:
Reaction of N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea with lead cyanamide bby the procedure of Example 121 gives N-cyano-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-N"-methylguanidine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1OC
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Br)nc1C(=O)O
Yield: 74.2 %

Procedure:
A solution of methyl 6-bromo-3-methoxypicolinate (3.0 g, 12.19 mmol) and LiOH.H2O (1.4 g, 33.36 mmol) in 1,4-dioxane/H2O (15 mL/15 mL) was stirred at RT overnight. The mixture was filtered and the filtrate was adjusted to pH=3 by aqueous HCl (2 M) and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product of 6-bromo-3-methoxypicolinic acid (2.1 g, yield: 73%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 10.05 (br s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.01 (s, 3H). MS (M+H)+: 232/234.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:12][CH2:13]Cl)[C:7](=[O:15])[C:6]=2[CH:16]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[Na+].C(N(CC)CC)C.C([O-])(=O)/C=C/C([O-])=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:12][CH2:13][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[N:17]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1c2cc(Cl)ccc2OC=CN1CCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(Cl)ccc2OC=CN1CCN1CCN(c2ncccn2)CC1
Yield: 67 %

Procedure:
14 mg of the compound of Example 1 was dissolved in 5 ml of dimethylformamide, 13 mg (1.5 equivalents) of 1-(2-pyrimidinyl)piperazine, 16 mg (2 equivalents) of sodium iodide, and 11 mg (2 equivalents) of triethylamine were added, and the resultant mixture was agitated at 90° C. for 10 hours. This was allowed to cool, then water was added and extraction was performed twice with ethyl acetate. The entire organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water, and saturated saline, then was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (methylene chloride:methanol=30:1) to obtain the above-referenced compound in an amount of 14 mg (yield of 67%). Note that the fumarate can be obtained by an ordinary method, then making it into an amorphous powder.
Reaction SMILES: [CH2:1]1[CH2:10][NH:9][CH2:8][C:7]2[C:6](=O)[NH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:1][C:2]=2[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[N:5]=1
Reactant: O=c1[nH]c2ccccc2c2c1CNCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2c2c1CNCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A slurry of 2,3,4,6-tetrahydrobenzo[c]-2,7-naphthyridin-5(1H)-one (43.1 g, 215 mmol) in POCl3 (260 mL) was vigorously stirred at reflux under nitrogen in a 2 L three-necked, round-bottomed flask equipped with a heating/cooling bath, mechanical stirrer, condenser, thermocouple, and nitrogen inlet. An aqueous base scrubber set-up was used to capture acidic exhaust gas. After 5 hours, the batch was homogeneous (indicating formation of the intermediate). Heating was continued for an additional 1 hour; then the mixture was allowed to slowly cool to ambient temperature and was stirred for 16 hours. When the starting material had been consumed, a 1 L addition funnel was fitted to the reaction flask, and the batch was cooled (ice-water) and carefully quenched by drop-wise addition of chilled water (˜1 L). The quench addition was completed in ˜6 hours. The resulting dark solution was stirred at ambient temperature for 18 hours. The batch was transferred to a 22 L round-bottomed flask equipped with a mechanical stirrer; the transfer was completed with water (13 L) to forestall salt precipitation that otherwise interferes with extraction. The pH was adjusted to 8.5-9 with aqueous 2 N sodium hydroxide (˜3.9 L). Product was extracted with 17% (v/v) tetrahydrofuran in 2-methyltetrahydrofuran (4×2 L). All organic layers were combined and washed with saturated aqueous sodium chloride (2×150 mL) and dried over anhydrous sodium sulfate (300 g). After removal of the drying agent, solvent was removed under reduced pressure at 35-40° C. The crude solid was swished with 10% (v/v) t-butyl methyl ether in diethyl ether (220 mL) for 1 hour (to remove BHT) and collected on a filter using the filtrate to complete the transfer. The filter cake was rinsed with 10% (v/v) t-butyl methyl ether in diethyl ether (40 mL) and diethyl ether (30 mL), and dried in a vacuum oven to constant weight. In this fashion the title compound was obtained as a light yellow solid of (41.6 g, 87% yield) of 96 A % purity by HPLC assay.
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.[NH:26]([C:28]1C=CC=CN=1)N>>[NH2:20][C:8]([NH:4][NH:3][C:2]1[CH:6]=[CH:5][CH:7]=[CH:28][N:26]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: NNc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)NNc2ccccn2)cc1

Procedure:
The compound of Example 9 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-hydrazinopyridine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 305.36; found mol. wt. (M+H) 306.1; 621.6 (Dimer)
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:15])=[C:7]([CH3:14])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:16]>C(Cl)(Cl)Cl.C(OCC)(=O)C.[Cu](Br)Br>[Br:16][CH2:12][C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH3:14])[CH:8]=1)=[O:13]
Reactant: Br
Reactant: CC(=O)c1cc(C)c(O)c(C(C)(C)C)c1
Agent: Br[Cu]Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 82.5 g (0.4 mol) of 1-(5-tert.butyl-3-methyl-4-hydroxyphenyl)-ethanone in 360 ml of chloroform was added dropwise while stirring to a suspension, heated to boiling, of 179 g (0.8 mol) of copper(II) bromide in 360 ml of ethyl acetate. The mixture was subsequently refluxed for 4 hours until the evolution of hydrogen bromide was complete. After the mixture had been cooled to room temperature, the copper salts were filtered off under suction, the filter residue was washed repeatedly with ethyl acetate, the filtrate was evaporated under reduced pressure, and the solid residue was recrystallized from cyclohexane.