Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:34][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 70.6 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 3-piperidin-1-yl-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 40:60-100:0) to give 0.035 g of 4-(3-chloro-phenyl)-2-[6-(3-piperidin-1-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.32) as a white powder. MH+/Z=496
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.S(O)(O)(=O)=O.[NH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:34]=[CH:35][N:36]=[C:32]1[NH:31][C:23]([C:22]1[C:16]2[O:15][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: Nc1ncc[nH]1
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2o1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2o1)c1cc2ccccc2cn1

Procedure:
Isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-benzooxazol-2-yl]-amide was synthesized according to General Procedure A using 137 mg (0.411 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid, 111 mg (0.822 mmol) 2-aminoimidazole sulfate, 171 mg (0.45 mmol) HBTU, 0.29 mL (1.65 mmol,) of DIEA and 2 mL of DMF stirring at 90° C. for 2 h. 98.9 mg (0.248 mmol, 60%) of the product was obtained. LCMS: 399 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[N:11]=1.CO.[OH-].[NH4+].[ClH:38]>CO>[ClH:9].[ClH:38].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:30])=[O:29])[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: NC(=O)c1cccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)c1
Reaction time: 5 h

Procedure:
400 mg of trans-1,4-diaminocyclohexane and 250 mg of the product obtained in Stage 1 above are taken to approximately 150° C., the reaction medium is left under agitation for 5 hours then left to return to ambient temperature for 16 hours. 8 ml of methanol is added, chromatography on silica is carried out (eluent: MeOH/NH4OH 98/2). The residue is taken up in an ethanolic solution of hydrochloric acid, followed by evaporating the solvents, impasting in ether, separating, drying under reduced pressure at ambient temperature and 101 mg of expected product is recovered.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1Br.[C:50]([Sn](CCCC)(CCCC)CCCC)#[N:51]>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.O1CCOCC1>[CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1[C:50]#[N:51]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2C#N)cc1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
Under Ar, compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (80 mg, 0.1 mmol) was mixed with Pd(PPh3)4 (12 mg, 0.01 mmol, Pd(t-Bu3P)3 (5 mg, 0.01 mmol), cyanotributylstannane (85 uL, 0.3 mmol) and dioxane (3 mL) in sealed tube. The resulting mixture was heated at 160° C. and stirred 2 hrs. After cooled to room temperature, the mixture was filtered through 10% KF on silica gel and washed with EtOAc. After concentration, the crude was used in the next step directly without further purification. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C38H46N6O4Si2 706.3, observed LCMS m/z 707.2 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:3][CH2:2]1.[H][H]>[C].[Pd].O1CCCC1>[NH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1NC1CCOCC1
Yield: 73.5 %

Procedure:
A 3-neck flask (200 mL) was charged with 1-(tetrahydropyran-4-yl)amino-2-nitro-4-trifluoromethylbenzene (see Synthesis Example 4-1) (1.00 g, 3.45 mmol) and tetrahydrofuran (17 mL), and this was shaken to give a homogeneous solution. To this was added palladium-carbon (Pd: 10%, 0.09 g), and this was again shaken. Hydrogen was substituted in by successively reducing the pressure and purging with hydrogen gas 3 times, and after vigorous shaking at room temperature under these conditions for 4 h, this was purged with nitrogen, distilled water (40 mL) was added and this was shaken for 10 minutes, then insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was further washed with ethyl acetate. The filtrate and wash solutions were combined and the solvent was distilled off under reduced pressure to yield the title compound (0.66 g, 73.6% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45](I)[CH:46]=1)[C:41]([OH:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(N(C)C)=O.O>[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[CH:46]=1)[C:41]([OH:43])=[O:42]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(O)c1cc(I)cc(F)c1NC1CCC(O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)O)c3)cc12
Temperature: 100 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.24 g, 3.27 mmol), 3-Fluoro-2-(4-hydroxy-cyclohexylamino)-5-iodo-benzoic acid (1.65 g, 3.27 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (66 mg, 0.08 mmol) in dimethylacetamide (20 mL) and aqueous solution of sodium carbonate (2M, 4.9 mL) was stirred at 100° C. for 14 h. The cooled reaction mixture was poured into 150 mL of water acidified with 6 N hydrochloric acid and filtered. The solids were redissolved in a mixture of dichloromethane and ethanol and filtered again. The filtrate was concentrated and the brown residue was purified by flash silica gel chromatography using a gradient of a solution of 90 parts ethyl acetate, 10 parts methanol, and one part acetic acid and hexanes afforded 1.5 g of a light brown solid (2.38 mmol, 76% yield). MS: m/z 630 [MH+]
Reaction SMILES: [CH:1]1([N:4]2[C:8]([O:9][CH2:10][C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=4)[N:15]=3)=[N:7][N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:3][CH2:2]1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:1]1([N:4]2[C:5]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:6][N:7]=[C:8]2[O:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:29]#[N:30])[N:15]=2)[CH2:3][CH2:2]1
Reactant: Ic1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from 4-{4-cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,4]triazol-3-yl}-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=1>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=3)[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: N#Cc1cc(Br)cs1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C2(CCCCC2)O1

Procedure:
Prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 4-bromo-2-thiophenecarbonitrile. A brown solid: mp 111-112° C.; 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.35 (dd, 1H, J=8.3, 1.1 Hz), 6.58 (d, 1H, J=8.4 Hz), 6.38 (s, 1H), 4.72 (m, 1H), 1.92-2.16 (m, 2H), 1.35-1.75 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 325 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1)C(OCC)=O)C.[OH-].[Na+]>CO>[Cl:17][C:16]1[C:11]([CH2:5][C:4]([OH:19])=[O:3])=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ncc(Cl)cc1Cl
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 2-(3,5-dichloro-pyrid-2-yl)-malonic acid diethyl ester (118.5 g) (prepared as described in WO 07/101,859) in methanol (1 ml) was added aqueous sodium hydroxide (47 g dissolved in 300 ml water). The reaction mixture was heated to 80° C. for 1 hour. The methanol was evaporated and the pH of the aqueous phase adjusted to pH 4 by addition of glacial acetic acid and then extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to give (3,5-dichloro-pyrid-2-yl)-acetic acid as an off-white solid (50 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 2H), 7.81 (d, 1H), 8.45 (d, 1H) ppm.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:15][O:14][C:5]1[C:6]2[CH2:7][CH2:8][CH:9]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]3)[CH2:10][CH2:11][C:12]=2[CH:2]=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: OC1CCCNC1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2c1CCC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCCC(O)C1)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.00 g, 0.00637 mol) and piperidin-3-ol (6 g, 0.06 mol) in methylene chloride (100 mL, 2 mol) at room temperature was added acetic acid (4 mL, 0.06 mol) dropwise. Molecular sieves (2 mass equiv) were added to the reaction mixture and the contents heated at 40° C. overnight. The reaction mixture was cooled to room temperature then at 0° C. in an ice bath. Sodium triacetoxyborohydride (7 g, 0.03 mol) was added in one portion as a solid. The reaction mixture continued to stir at 0° C. for 1 h then warmed to room temperature for 4 h Workup involved quenching with water, adjusting the pH to 8-10 with 10 N NaOH (aq) and extracting with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark oil. Purification involved ISCO chromatography on silica gel (40 g column) using methylene chloride-methanol with 5% ammonium hydroxide. Fractions corresponding to product (polar fractions) were combined and concentration to give 1-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperidin-3-ol as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 3.86 (s, 4H), 3.47 (m, 3H), 2.88 (t, 1H, J=11 Hz), 2.60-2.70 (m, 4H), 2.48-2.41 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H), 1.59 (m, 3H), 1.26-1.39 (m, 2H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([S-:44])[CH3:43].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C=O)C.CCOC(C)=O>[CH2:42]([S:44][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1)[CH3:43]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC[S-]
Agent: [Al+3]
Agent: [Na+]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
(R)-1-(3-Bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Intermediate 14B; 59 mg, 0.098 mmol), sodium ethanethiolate (20.59 mg, 0.245 mmol), and aluminum oxide (100 mg, 0.979 mmol) were dissolved in DMF (2 mL) and heated in a microwave reactor to 100° C. for 2 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (7-60% EtOAc/hexane) to give (R)-1-(3-(ethylthio)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C36H33N5OS [M+1]+ 584. found 584.
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (100 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol) and then Tf2O (186 mg, 0.66 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][OH:19].Cl>O.C(Cl)(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([OH:12])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: OCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)O)ccc1OCCCO

Procedure:
Vanillic acid (C1) (114.5 g, 0.68 mol) was dissolved in a solution of sodium hydroxide (54.5 g, 1.36 mol) in water (400 mL). 3-Bromopropan-1-ol (101.3 g, 0.73 mol, 1.07 eq) was added and the mixture was heated under reflux for 5 hours. The mixture was cooled and acidified with 2.5 M HCl. The resulting precipitate was filtered and dried under vacuum. Recrystallisation from butan-2-one gave the product as an off white solid. (110 g, 71%). mp: 162° C.; 1H NMR (DMSO-d6, 400 MHz) δ 7.56 (dd, 1H, J=1.98 Hz, J=8.39 Hz), 7.44 (d, 1H, J=1.96 Hz), 7.04 (d, 1H, J=8.50 Hz), 4.55 (bs, 1H), 4.09 (t, 2H, J=6.37 Hz), 3.80 (s, 3H, OMe), 3.57 (t, 2H, J=6.20 Hz), 1.88 (p, 2H, J=6.29 Hz); 13C NMR (100 MHz, DMSO-d6) δ167.1, 152.0, 123.1, 122.7, 112.0, 111.7, 65.3, 57.2, 55.4, 31.9; IR (CHCl3) 1673, 1596, 1585, 1517, 1425, 1271, 1227, 1188, 1134, 1051, 1026, 951, 876, 814, 758 cm−1; MS (ES−) m/z (relative intensity) 225.04 ([M−H]−, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:18]Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([Br:18])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(O)c(Br)c1)OCC
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of (S)-2-ethoxy-3-(4-hydroxyphenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No 19, 3139–3142, 1994) (9.5 g, 40 mmol) in dry methylene chloride (100 ml) was over 1 h dropwise added a solution of bromine in methylene chloride (40 ml) at room temperature. The reaction was stirred for 60 min, washed with saturated sodium sulfite and brine. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (9:1) as eluent to give 11.25 g (88%) of (S)-3-(3-bromo-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[C:15]1([NH:14][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1c[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), aniline (0.46 mL, 5^ mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (959 mg, 5 mmol) in 50% aqueous dioxane (10 mL) was allowed to stir at ambient temperature for 17.5 hours, then concentrated in vacuo. The residue was cooled in an ice water bath, aqueous 3.6 N hydrochloric acid was added, and the precipitate collected, rinsed with aqueous 3.6 N hydrochloric acid then water and dried. Recrystallization from ethyl alcohol afforded N-phenyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 35) (164 mg). mp 225-226° C.
Reaction SMILES: Br.[C:2]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O>[C:2]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CC(=O)N1CCNCC1
Reactant: C=C(C)C(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)N1CCN(C(=O)CC(C)=O)CC1
Reaction time: 20 h
Yield: 56 %

Procedure:
Crude 1-acetoacetylpiperazine hydrobromide (50 g, 0.2 mole) was dissolved in N,N-dimethylformamide (300 ml) with AranoxTM (50 mg) (available from U.S. Rubber Co.). Triethylamine (50 g, 0.5 mole) was added at 0° C., followed immediately by the dropwise addition of methacryloyl chloride (20.8 g, 0.2 mole) at 0° C. The reaction solution was then allowed to reach 20° C. over a 20 hour period. The reaction solution was filtered and the solvent was removed at low vacuum. The residue was distilled to give 4-acetoacetyl-1-methacryloylpiperazine (b.p.=110°-129° C./10-8μ) at a yield of 56%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[CH:22]OCC)#[N:20].[ClH:26].C(O)C>C(O)C.C(OCC)C>[ClH:26].[C:19]([NH:21][CH:22]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)#[N:20]
Reactant: CCOC=NC#N
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: N#CNC=NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a solution of 2.48 g of 3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine (prepared according to British Pat. No. 2,023,123 which is hereby incorporated by reference) in 25 ml of absolute ethanol, are added dropwise 0.98 g of ethyl N-cyano-formimidate in 15 ml of ethanol, under stirring and at room temperature. Stirring is maintained for 30 minutes, and then the ethanol is removed by underpressure distillation. An oil residue is formed, which is then dissolved in 250 ml of ethyl ether, after which 0.95 ml of 10N HCl/ethanol are added, yielding 1.4 g of N-cyano-N'-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formamidine hydrochloride.