Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:2]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=Cc1csc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: c1ccc(N2CCN(Cc3csc4ccccc34)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Benzothiophene-3-carbaldehyde (6.17 mmole), 1-(2-pyridinyl)piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2-dichloroethane and stirred at 0° C. for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether:dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography with 96:4:0.5 dichloromethane/methanol/saturated aqueous ammonia to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.62 (t, 4H, J=4.5 Hz), 3.51 (t, 4H, J=4.5 Hz), 3.82 (s, 2H), 6.65 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 7.40 (m, 2H), 7.48 (s, 1H), 7.53 (m, 1H), 7.86 (m, 1H), 8.04 (m, 2H); MS (DCI/NH3) m/z 310.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=2)[CH2:30][CH2:31]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 40 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 40%). MS (m/e): 502.0 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=1)=[N:6]2.[CH:33](B(O)O)=[CH2:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:4]1[N:5]2[C:10]([CH:9]=[N:8][C:7]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:6]2)=[C:2]([CH:33]=[CH2:34])[CH:3]=1
Reactant: C=CB(O)O
Reactant: COc1ccccc1-c1cc(Br)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
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: CN(C)C=O
Product: C=Cc1cc(-c2ccccc2OC)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Temperature: 140 °C

Procedure:
Into a 30 mL vial [5-Bromo-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (90.0 mg, 0.000182 mol), Vinyl boronic acid (100 mg, 0.002 mol), Potassium carbonate (1.12 g, 0.00814 mol), and Tetrakis(triphenylphosphine)palladium (0) (21.3 mg, 0.0000184 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. N,N-Dimethylformamide (5 mL, 0.06 mol) was added. The reaction mixture was heated at 140° C. for 4 hours. The reaction was partitioned with water and EtOAc. The organic was separated and washed with water. Subsequently the organic was washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and Methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(2-Methoxy-phenyl)-5-vinyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine a yellow solid (68 mg, 85%). MP 150-151° C. LCMS (E/I+) 441.24 (M+H). NMR 1H (DSMO-d6)-9.17 (s, 1H), 9.14 (s, 1H), 7.75 (dd, 1H, JJ=1.60, 6.04 Hz), 7.53 (d, 2H, J=8.96 Hz), 7.48 (dt, 1H, JJ=1.52, 6.92 Hz), 7.22 (d, 1H, J=8.36 Hz), 7.00-7.18 (m, 3H), 6.78 (d, 2H, J=9.04 Hz), 5.78 (d, 1H, J=17.56 Hz), 5.24 (d, 1H, J=11.81 Hz), 3.80 (s, 3H), 3.02 (t, 4H, J=4.56 Hz), 2.44 (t, 4H, J=4.68 Hz), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH:6]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methoxybenzenesulfonyl chloride.
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[C:29]1(=[O:55])[N:33]([CH2:34][CH2:35][CH2:36][NH:37][CH:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[O:48][CH3:49])[O:40][CH2:39]2)[C:32](=[O:50])[C:31]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:30]12>>[CH2:1]([N:37]([CH:38]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][C:45]=2[O:48][CH3:49])[O:40][CH2:39]1)[CH2:36][CH2:35][CH2:34][N:33]1[C:32](=[O:50])[C:31]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:30]2[C:29]1=[O:55])[CH2:2][CH3:27]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCN1C(=O)c3ccccc3C1=O)CO2
Product: CCCN(CCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Yield: 76 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 3, the expected product is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1([CH3:28])[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21]2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]1=2>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[C@@H:22]4[C@@H:17]([C:16]5[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=5[C:14]([CH3:28])([CH3:13])[CH2:23]4)[CH2:18][CH2:19][CH2:20]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1(C)C[C@@H]2NCCC[C@@H]2c2ccccc21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: CC1(C)C[C@H]2[C@H](CCCN2C(=O)c2ccc3[nH]cnc3c2)c2ccccc21
Yield: 58 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=2.84 min; Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:24][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1)[CH:22]=[O:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1coc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of 4-chloromethyl-2-phenyloxazole (10.0 g), vaniline (7.9 g), potassium carbonate (8.6 g) and N,N-dimethylformamide (DMF) (90 ml) was stirred for 2 hours at 100° C. The reaction mixture was poured into ice-water. Resulting crystalline precipitate was collected by filtration, which was dissolved in chloroform (400 ml). The chloroform layer was washed with water, dried (MgSO4) and concentrated. Residual crystalline product was collected by filtration to yield 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)benzaldehyde (15.4 g, 97%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.119-120° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][OH:16])[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([C:29](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][O:16][C:29]([C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1OC[C@H](OCc2ccccc2)[C@@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of 1,4-anhydro-2-O-benzyl-D-ribitol (1.0 g, 4.46 mmol) in pyridine (20 mL, 247 mmol) was added 4,4′-dimethoxytrityl chloride (4.53 g, 13.38 mmol). The mixture was stirred at ambient temperature for 2 h. Solvent was then evaporated in vacuo, and the residue purified by flash chromatography using 25-30% ethyl acetate in hexane to obtain 1.65 g (3.13 mmol, 70%) of the pure product. LCMS: for C33H34O6 calculated 526.2. found 549.2 [M+H]+. 1H NMR (600 MHz, CD3CN) δ: 7.42, (m, 2H), 7.37 (m, 4H), 7.30 (m, 7H), 7.21 (tt, J=7.3, 1.1 Hz, 1H), 6.85 (m, 4H), 4.61 (d, J=3.4 Hz, 2H), 4.05 (dd, J=9.9, 4.7 Hz, 1H), 4.01 (m, 2H), 3.81 (m, 2H), 3.76 (s, 2H), 3.76 (s, 6H), 3.17 (dd, J=10.2, 3.2 Hz, 1H), 3.00 (dd, J=10.2, 5.0, 1H), 2.97 (s, 1H). 13C NMR (600 MHz, CD3CN) δ: 158.84, 130.21, 128.59, 128.27, 128.01, 127.88, 126.98, 117.53, 113.22, 82.73, 78.59, 72.28, 71.87, 70.21, 64.44, 55.11.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(=O)n(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Yield: 51 %

Procedure:
Diethyl 1,2-dihydro-2-oxo-1-phenylquinol-4-ylmalonate (2.7 g.) was dissolved in ethanol (50 ml.), and a solution of sodium hydroxide (2.85 g.) in water (3 ml.) was added. The mixture was heated under reflux for 1 hour, and then cooled and poured into water (200 ml.) to give a solution which was treated with decolourising carbon, filtered, and adjusted to pH 3 by addition of hydrochloric acid. The precipitate was collected by filtration, washed with water, drained, and crystallised from methanol to give 1,2-dihydro-2-oxo-1-phenylquinol-4-ylacetic acid, m.p. 185.5°-186° C. (decomposition), in 51% yield.
Reaction SMILES: [ClH:1].[CH2:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:3]1[N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[ClH:1].[CH2:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:3]1[N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:17]([CH3:31])[C:16]2=[O:26])[CH2:14][CH2:13]1
Reactant: CI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCC3CCCCC3C1)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CN(c2ccccc2)C2(CCN(C3CCC4CCCCC4C3)CC2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
8-(Decahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride (1:1) (1.2 mmol) was suspended in DMF (20 ml). Sodium hydride (2.4 mmol) was added and the mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature, methyl iodide (1.2 mmol) was added and the mixture was stirred for 18 h. DMF was evaporated, sodium bicarbonate and ethylacetate were added. The organic phase was washed with brine, dried with MgSO4 and concentrated. Chromatography on silica gel (methylenchloride/methanol, 98:2) yielded the desired product which was crystallized as its HCl-salt from ethylacetate/ethanol. 0.19 g (36%) 8-(decahydro-naphthalen-2-yl)-3-methyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride (1:1) as a colorless solid, m.p.>250° C. and MS: m/e=382 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.O1CCOCC1.O.C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:15])[CH3:25]
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 6-bromo-N-((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.37 g, 0.85 mmol) and 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) in dioxane/water mixture (3 mL+1 mL for 1 mmol), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.05 equiv.) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound. (38% yield). LCMS: 491.25 (M+1)+; HPLC: 95.01% (@ 254 nm) (Rt; 5.463); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.87 (s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 6.80 (s, 1H), 5.91 (s, 1H), 5.22-5.19 (m, 1H), 4.39 (d, 2H, J=4.0 Hz), 2.42-2.40 (m, 4H), 2.24 (s, 3H), 1.49 (d, 6H, J=6 Hz). 1.24 (s, 6H), 1.14 (s, 6H), 1.11 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[F:26]C1C=CC(N)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:26])=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 138 steps (a) and (b) for the synthesis of 2,3-dibromo-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 4-fluoroaniline. The title compound, ESI MS (m/z): 457 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][CH2:49][OH:50]>CN(C)C=O>[OH:50][CH2:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:36])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (360 mg, 0.70 mmol) (Example 22(a)) was dissolved in dimethylformamide (2.1 ml) . Sodium iodide (15 mg, 1 mmol), triethylamine (142 mg, 1.4 mmol) and 3-chloro-1-propanol (132 mg, 1.4 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 3 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (3 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the dichloromethane solution and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (6 ml). The aqueous solution was washed with ether (6×3 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 192 mg (68%), FAB MS: 405(M+1). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:25]3[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]3)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.1 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.15 g, 5.4 mmol) in NMP (4 mL) and TEA (0.5 mL) was added 1-Boc-piperazine (1.05 g, 5.64 mmol). The mixture was microwaved at 100° C. for 30 minutes and then diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was subject to chromatography on silica gel, eluting by hexanes/ethyl acetate (2:1-1:1) to afford the tert-butyl 4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.47 g, 75%). 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 5.99-5.96 (m, 1H), 3.78-3.73 (m, 2H), 3.53-3.50 (m, 2H), 3.15-3.07 (m, 1H), 2.99-2.92 (m, 1H), 2.63-2.54 (m, 1H), 2.04-1.93 (m, 1H), 1.48 (s, 9H). MS (APCI+) [M+H]+363.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].B1([C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)OCCCO1>>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Product: COc1ccc([N+](=O)[O-])cc1-c1cccnc1
Yield: 76.1 %

Procedure:
2-Bromo-4-nitroanisole (3.0 g, 12.9 mmol) was reacted with pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.53 g, 15.5 mmol) over 8 hours, as described in Example 62. The resulting crude residue was purified by column chromatography on silica, using 60-70% diethyl ether in dichloromethane as the eluent, to yield 3-(2-methoxy-5-nitrophenyl)pyridine (2.26 g, 85%): δH (360 MHz, d6-DMSO) 3.94 (3H, s), 7.39 (1H, d, J 9.2), 7.50 (1H, dd, J 7.9 and 4.8), 7.97 (1H, dt, J 8.0 and 1.9), 8.19 (1H, d, J 2.8), 8.33 (1H, dd, J 9.2 and 2.8), 8.57-8.64 (1H, m), 8.74 (1H, d, J 1.9).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[CH3:28][C:29]1[C:33]([NH2:34])=[C:32]([CH3:35])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([NH:34][C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=2)=[O:12])=[C:32]([CH3:35])[O:31][N:30]=1
Reactant: Cc1noc(C)c1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Product: CCc1cc2c(C(=O)Nc3c(C)noc3C)cnc(OC(F)F)c2o1
Yield: 9.7 %

Procedure:
This Example was conducted following the procedure of Example 1, but starting from 7-difluoromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 3,5-dimethylisoxazol-4-ylamine (118 mg). Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane followed by trituration in diethyl ether afforded the title compound as an off-white solid (18 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[C:33]2[C:24](=[N:25][C:26]3[C:27](=O)[CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=2)[C:23](=O)[CH2:22][CH2:21]1>>[C:14]1([C:10]2[CH:11]=[CH:12][CH:13]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]=2[N:9]=[C:23]2[C:24]3[C:33](=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][C:27](=[N:9][C:8]5[C:10]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)=[CH:11][CH:12]=[CH:13][C:7]=5[C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]=4[N:25]=3)[CH2:20][CH2:21][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Reactant: Nc1c(-c2ccccc2)cccc1-c1ccccc1
Product: c1ccc(-c2cccc(-c3ccccc3)c2N=C2CCCc3cc4c(nc32)C(=Nc2c(-c3ccccc3)cccc2-c2ccccc2)CCC4)cc1

Procedure:
was synthesized by methods similar to those in Examples 3 and 4: 2,6-diphenylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[2,6-diphenylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (6). Complexation of (6) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of final complex was proved by direct probe GC. Exact mass direct probe calculated for C49H39Cl2FeN3: 795.19. Found: 795.19.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][CH:9]([CH3:10])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-oxopentanoate (5.00 g, 34.7 mmol) in chloroform (27 mL) at 0° C. was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, concentrated to give ethyl 4-bromo-3-oxopentanoate. 1HNMR (500 MHz, CDCl3), δ4.670-4.630 (dd, J=6.7 Hz, 1H), 4.251-4.208 (dd, J=7.2 Hz, 2H), 3.883-3.851 (d, J=16 Hz, 1H), 3.687-3.655 (d, J=16 Hz, 1H), 1.804-1.791 (d, J=6.8 Hz, 3H), 1.323-1.295 (m, J=7.2 Hz, 3H).