Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:25]O>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][CH:19]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:25])=[O:10]
Reactant: CO
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)OC)cc1

Procedure:
A solution of 3 g of 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoic acid, the product of Example 7b, 40 ml of MeOH, 40 ml of toluene and 3 drops of BF3 ·Et2O was heated for 12 hr to reflux with a Dean Stark trap to remove water. Solvent was removed and the residue was dissolved in Et2O and was washed NaHCO3 solution and NaCl solution. The ether solution was dried over MgSO4 and removed solvent to give the title compound, an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[C:22](#[N:24])[CH3:23].CC(N(C)C)=O>>[CH3:23][C:22]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:24]=1
Reactant: CC#N
Reactant: CC(=NO)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccc(O)cc2o1
Temperature: 22.5 °C

Procedure:
To a mixture of 1-(2,4-dihydroxy-phenyl)-ethanone oxime (4.2 g, 25 mmol) and acetonitrile/dimethylacetamide (20 mL, 3:1) cooled by a water bath (20-25° C.) was added dropwide phosphorus chloride (2.4 mL, 26.2 mmol) over a period of fifteen minutes. The mixture was stirred for an additional thirty minutes before it was poured into ice water containing sodium acetate (6 g). The mixture was stirred for ten minutes, filtered, and the filter cake was washed with water and dried in vacuo to give the title compound as a yellow solid (3.15 g): 1H NMR (CDCl3, 200 MHz): δ=7.45 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromoheptane (0.199 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+382.2 (M+H)+, HRMS calcd for C23H32N3O2 382.2495 (M+H)+, found 382.2489, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.6 min, 98.6% purity.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][C:6]3[N:18]([CH3:19])[CH:17]([CH3:20])[C:16]([CH3:22])([CH3:21])[C:7]=3[CH:8]=2)[NH:3]1.P(OC)(OC)(O[CH3:26])=O>>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]2[C:4](=[CH:5][C:6]3[N:18]([CH3:19])[CH:17]([CH3:20])[C:16]([CH3:21])([CH3:22])[C:7]=3[CH:8]=2)[N:3]1[CH3:26]
Reactant: CC1N(C)c2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2C1(C)C
Reactant: COP(=O)(OC)OC
Product: CC1N(C)c2cc3c(cc2C1(C)C)c(C(F)(F)F)cc(=O)n3C

Procedure:
refluxing said 7-oxo-1,2,3,3-tetramethyl-5-trifluoromethyl-2,3,7,8-tetrahydro-1H-pyrrolo [3,2-g] quinoline with trimethyl phosphate to yield 7-oxo-1,2,3,3,8-pentamethyl-5-trifluoromethyl-2,3,7,8-tetrahydro-1H-pyrrolo [3,2-g] quinoline.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[O:12]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:12]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(OCC2CNCCO2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCC2CN(Cc3nc4ccccc4[nH]3)CCO2)cc1
Yield: 66 %

Procedure:
2-(Chloromethyl)benzimidazole (172 mg, 1.03 mmol) and 2(RS)-(phenoxymethyl)morpholine (200 mg) were heated in ethanol (8 ml) at 80° C. (oil bath temperature) in the presence of potassium carbonate (142 mg, 1.03 mmol) for 2 hours. The mixture was cooled then evaporated to dryness. The residue was partitioned between water (10 ml) and ethyl acetate (25 ml). The organic layer was separated and the aqueous re-extracted with ethyl acetate (25 ml). The combined organics were dried (sodium sulphate) then evaporated to give a beige gum which was purified by column chromatography on silica (150 g) using ethyl acetate to ethyl acetate/methanol (25:1) to afford the title compound as a pale yellow solid (220 mg, 66%). mp 171°-172° C. (ethyl acetate/n-hexane). MS, CI+, mz=324 for (M+H)+. 1H NMR (360 MHz, CDCl3) δ2.40 (1H, dd, J1 =J2 =10 Hz), 2.51 (1H, ddd, J1 =3, J2 =J3 =10 Hz), 2.79 (1H, d, J=10 Hz), 2.99 (1H, d, J=10 Hz), 3.82 (1H, ddd, J1 =3, J2 =J3 =10 Hz), 3.91-4.06 (6H, m), 6.88 (2H, dd, J1 =1, J2 =8 Hz), 6.95 (1H, ddd, J1 =1, J2 =J3 =8 Hz), 7.24-7.29 (4H, m), 7.57-7.61 (2H, m). Found: C, 70.55; H, 6.51; N, 12.96. C19H21N3O2 requires C, 70.57; H, 6.55; N, 12.99%.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:2]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:16][C:13](=[O:15])[CH3:14])[C:2]=12
Reactant: [O-][n+]1cccc2c1CCCCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCCCc2cccnc21
Temperature: 90 °C

Procedure:
The N-oxide was dissolved in acetic anhydride (222 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated. Distillation (Kugelrohr, bp 110-140° C. @ 1 Torr) of the resultant oil provided 53.26 g of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([S:38]([CH2:41][CH2:42][NH:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:32]1([S:38]([CH2:41][CH2:42][N:43]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH3:49])[CH2:50][CH3:51])(=[O:40])=[O:39])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCN(CC)CCCNCCS(=O)(=O)c1ccccc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: CCN(CC)CCCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N′-(2-benzenesulfonyl-ethyl)-N,N-diethyl-propane-1,3-diamine (139 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 730 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[N:18]=1)[C:5]([CH:7](C(OC)=O)C(OC)=O)=[O:6].O>CS(C)=O>[C:5]([C:4]1[CH:3]=[C:2]([Cl:1])[N:18]=[C:17]([Cl:19])[CH:16]=1)(=[O:6])[CH3:7]
Reactant: COC(=O)C(C(=O)OC)C(=O)c1cc(Cl)nc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1328 g (4.34 mol) of dimethyl 2,6-dichloro-isonicotinoyl-malonate are dissolved in a mixture of 3.45 l of dimethyl sulphoxide and 156.2 g (8.68 mol) of water. The reaction mixture is heated to 140° C. and stirred at this temperature for 30 minutes. After this, the reaction mixture is cooled to 10° C. and then added to 8.4 l of ice-water. The mixture is extracted twice with a total of 3.6 l of dichloromethane and the combined organic phases are washed once with 1.5 l of saturated, aqueous sodium hydrogen carbonate solution. After drying over sodium sulphate, the organic phase is concentrated under reduced pressure. The residue which remains is distilled under reduced pressure. In this manner 506.0 g (60% of theory) of 4-acetyl-2,6-dichloropyridine of boiling point 98° C. at 0.5 mbar are obtained. ##STR36##
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40](B(O)O)[CH:39]=1>O1CCOCC1.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:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:40]4[CH:39]=[C:38]([F:37])[CH:43]=[CH:42][N:41]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccn1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
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: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(-c2cc(F)ccn2)cc1
Temperature: 25 °C

Procedure:
To a degassed, stirred mixture of [5-(4-bromo-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (150 mg, 0.30 mmol) in 1,4-dioxane (10 mL) and a 1 M aqueous solution of potassium carbonate (0.89 mL, 0.89 mmol) was added 4-fluoro-pyridine-2-boronic acid (51 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) under argon at room temperature. The mixture was heated at reflux for 4 hours. After being cooled to room temperature, the solvents were removed under reduced pressure. The crude residue was diluted with ethyl acetate (50 mL), washed with water (10 mL×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude {5-[4-(4-fluoro-pyridin-2-yl)-benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester, which was used without further purification. MS cald. for C27H29FN2O5S 512, obsd. 513 [(M+H)+].
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][CH:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nn2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nn2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 0.3-chloroperbenzoic acid (0.38 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred at −78° C. for 4 hours and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylsulfinyl]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 70) (0.14 g) as yellow amorphous.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1cccc(O)n1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 18.7 g (0.17 mol) of 6-hydroxy-2-methylpyridine (commercially available) and 24.0 g (0.17 mol) of n-butyl bromide dissolved in 100 ml of dimethylformamide was added 23.0 g (0.17 mol) of potassium carbonate, and the mixture was stirred at 90°-110° C. for 8 hours. To the mixture was added 300 ml of ice-water, and the mixture extracted with ethyl acetate, followed by a separation of the oily extract obtained by silica gel chromatography (ethyl acetate:hexane=7:97) to give 19.8 g of an oily substance (yield 69.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[Cl:11][CH2:12][CH2:13][NH:14][CH:15]([CH2:18][O:19][CH3:20])[CH:16]=[O:17]>C1C=CC=CC=1>[Cl:11][CH2:12][CH2:13][N:14]([CH:15]([CH2:18][O:19][CH3:20])[CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10]
Reactant: COCC(C=O)NCCCl
Reactant: COc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: COCC(C=O)N(CCCl)C(=O)Nc1nnc(OC)s1

Procedure:
5-Methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-β-chloroethylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-β-chloroethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][C:21]([NH:23][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:22])=[CH:17][CH:16]=1
Reactant: NC(=O)NCc1ccc(Cl)cc1
Reactant: N#CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)NC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
68.7 g of 98% cyanoacetic acid and 155 ml of acetic anhydride were kept at 65° C. for 30 minutes. 4-chlorobenzylurea (132.9 g) was added in portions over 10 minutes. After 2 hrs. at 70-75° C., further acetic anhydride (25 ml) was added. After a further 15 minutes,90 ml of toluene was added, cooled to room temperature, the solid collected and washed with toluene to give the title compound (155.60 g) as a white-solid mp 203-6° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
To a solution of 4-iodo-1H-pyrazole (5 g, 25.78 mmol, 1.0 eq.) in DMF (25 ml) were added K2CO3 (8.908 g, 64.45 mmol, 2.5 eq.) and bromocyclopentane (4.96 g, 33.51 mmol, 1.3 eq.). The mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to give the product in 89.5% yield. 1H NMR (300 MHz, CDCl3): δ 7.49 (s, 1H), 7.45 (s, 1H), 4.66-4.62 (m, 1H), 2.17-2.02 (m, 1H), 2.00-1.96 (m, 2H), 1.93-1.78 (m, 2H), 1.73-1.67 (m, 2H). LC-MS (ESI): Calculated mass: 262; Observed mass: 263 [M+H]+ (rt: 1.57 min).
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([OH:33])[CH:32]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([O:33][S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[CH:32]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1c(-c2cncc(O)c2)cc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)N1CCCC1
Product: CC(C)(C)OC(=O)n1c(-c2cncc(OS(=O)(=O)N3CCCC3)c2)cc2ccc(Cl)cc21

Procedure:
1-Pyrrolidine-sulfonyl chloride and 6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester (Example 160a) are processed according to the method described in Example 160b to give 6-chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, which is taken onto the next step without further purification. MS (ESI) m/z 478.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:15]2[CH:14]([C:16]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:12]1[C:13]2[CH:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:15]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CNC(=O)C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)C1c2ccccc2-c2ccccc21
Yield: 54.1 %

Procedure:
4.2 ml of 1N sodium hydroxide was added dropwise under ice-cooling to a solution of 900 mg of methyl N-(9-fluorenylcarbonyl)glycinate in 55 ml of ethanol. The resultant mixture was stirred at room temperature for 1.5 hours. The residue obtained by concentrating the reaction mixture was dissolved in 0.5N sodium hydroxide, and washed with an ether. Under ice-cooling, the pH value of the aqueous layer was adjusted to 3 to 4 with 5% hydrochloric acid, and the precipitate formed was separated by filtration. The precipitate thus separated was washed with water and, then, recrystallized from a mixture of ethanol and ether to give 463 mg of N-(9-fluorenylcarbonyl)glycine as white needles.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1([CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:8].[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]1([CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C(=O)c3ccccn3)CCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2(C(O)c3ccccn3)CCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example 265D (140 mg, 0.43 mmol) in THF (4 mL) and MeOH (4 mL) was added NaBH4 (60 mg, 2.5 mmol) and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and the resulting mixture extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to obtain the title compound (0.11 g, 76% yield) as a white solid. MS: m/z 333 (M+H); 1H NMR: (400 MHz, CDCl3): δ 8.57 (d, J=4.3 Hz, 1H), 7.67 (t, J=6.8 Hz, 1H), 7.31-7.23 (m, 2H), 4.73 (s, 1H), 4.55-4.43 (m, 1H), 3.56-3.26 (m, 2H), 3.13-2.79 (m, 2H), 2.28-2.07 (m, 3H), 2.05-1.85 (m, 2H), 1.75-1.70 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][NH2:21])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)C(=NN)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a hot solution of 10 g 4,4'-dimethylbenzil in 20 ml of ethanol is added 2.1 g of hydrazine hydrate. After a few minutes at reflux, a solid begins to crystallize. Heating is continued for 10 min. and the solution cooled slowly to 0° C. The solid is filtered off and washed with cold ethanol. The product is recrystallized from ethanol. Yield 7.1 g. M.P. 137°-140°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[CH2:29][CH2:28]OCC1>O>[CH3:10][NH:11][C:12]1[N:15]=[CH:29][C:28]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 61 %

Procedure:
A solution of Example A1 (0.380 g, 1.510 mmol) and 6-(methylamino)-3-pyridinylboronic (0.252 g, 1.661 mmol) in dioxane (8 mL) was sparged with Ar, treated with a solution of K2CO3 (0.417 g, 3.02 mmol) in water (2 mL) and heated at 90° C. for 16 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-methyl-4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-amine (300 mg, 61%) as an orange amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J=2.5 Hz, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.39 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.8, 2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.9 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.00 (dd, J=5.6, 2.3 Hz, 1H), 6.87 (q, J=5.2 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 2.80 (d, J=4.7 Hz, 3H); MS (ESI) m/z: 324.1 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20](CC2C=CC=CC=2)[N:19]=[N:18][N:17]=1)=O)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:20][N:19]=[N:18][N:17]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1nnnn1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C1CN[C@H](c2nnn[nH]2)C1
Reaction time: 6 h

Procedure:
To a solution of 494 mg (S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester in 50 ml ethanol were added 100 mg Pd(OH)2/C (10%) and the suspension stirred under an atmosphere of hydrogen (4 bar) for 6 h. The reaction mixture was filtrated over a plug of Celite® and washed with ethanol. Yield: 173 mg colorless foam.