Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([O:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]3[CH2:40][NH:39][CH2:38][CH2:37][C:35]=3[N:36]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([O:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]3[CH2:40][N:39]([C:10]([C:3]4[CH:2]=[N:1][N:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=45)=[O:12])[CH2:38][CH2:37][C:35]=3[N:36]=2)=[CH:27][CH:26]=1
Reactant: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CNCC2
Reactant: O=C(O)c1cnn2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
A suspension of the pyrazolo[1,5-a]pyridine-3-carboxylic acid (9.45 g, 58.3 mmol) and N,N-dimethylformamide (0.451 mL, 5.83 mmol) in CH2Cl2 (600 mL) was cooled to 0° C. and treated slowly with oxalyl chloride (7.65 mL, 87 mmol). The mixture was removed from the cold bath and stirred at room temperature for 2.5 h. An LC-MS sample with added pyrrolidine indicated no residual starting material. The mixture was filtered through filter paper to remove undissolved precipitates and then concentrated in vacuo to afford the crude acid chloride as a tan solid. This tan solid was re-dissolved in CH2Cl2 (300 mL), and added via an addition funnel over two minutes to a stirring solution of 2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (16.08 g, 115 mmol) in CH2Cl2 (300 mL) at 0° C. The reaction mixture was removed from the cold bath and stirred for 30 min. The reaction mixture was diluted with CH2Cl2 (1.2 L) and washed with water (1.5 L) and sat. aq. NaHCO3 (1.5 L). The organic phase was washed with brine (1 L) and the aqueous phases were back-extracted with CH2Cl2 (0.5 L). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting orange amorphous foam was purified by gradient elution on silica gel 0 to 50% [10% MeOH in DCM] in DCM. The isolated amorphous material was diluted with EtOAc (600 mL) and crystallized out of solution at room temperature. The mixture was stirred at 60° C. for 45 min and concentrated to dryness to drive all of the amorphous material to the crystalline form. The now crystalline material was stirred with diethyl ether (1 L) for 30 min at room temperature and then triturated. The resulting white solid was washed with diethyl ether (3×100 mL) and dried to afford the title compound as a white crystalline solid (25.16 g, 94%). Data for O-2: 1H NMR (500 MHz, CDCl3) δ 9.16 (d, J=2.4, 1H), 8.61 (dd, J=8.3, 2.5 Hz, 1H), 8.53 (d, J=6.8, 1H), 8.18 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.35 (td, J=7.9, 1.0 Hz, 1H), 6.95 (td, J=7.0, 1.2 Hz, 1H), 4.89 (s, 2H), 4.68 (t, J=4.8 Hz, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.80 (t, J=4.8 Hz, 2H), 3.44 (s, 3H), 3.11 (t, J=5.7, 2H); HRMS m/z (M+H) 465.1446 found, 465.1436 required.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11].C1C=CC=CC=1>O1CCCC1>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of H2PtCl6 /THF. Into the same apparatus as described in Example 1 were added 1 g of bis(dichlorosilyl)methane, 20 μl of 0.1 M H2PtCl6 in THF (tetrahydrofuran) solution, and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a ten minute period. The flask content was refluxed, with stirring, for another 8 hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 1.66 g of 3,3,5,5-tetrachloro-1-phenyl-3,5-disilapenta-1-ene (TCD-GC area 27.3%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 26.4%).
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:19]I.O>O1CCCC1>[CH3:1][S:2][C:3]([CH3:19])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(C)(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 59.5 %

Procedure:
To 2.02 g of 2-methylthio-4'-(trifluoromethyl)propiophenone dissolved in 20 ml of tetrahydrofuran was added under ice-cooling 0.33 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 1.27 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography using n-hexane to obtain 1.27 g of an oily product of 2-methylthio-4'-(trifluoromethyl)isobutyrophenone (yield: 59.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][OH:13]>>[CH3:8][N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CNCCCO
Reactant: Clc1ccncc1
Product: CN(CCCO)c1ccncc1
Yield: 2560.8 %

Procedure:
Using a procedure analogous to that described for the starting material in Example 46, 4-chloropyridine (885 mg, 59 mmol) and 3-(methylamino)propanol (2.1 g, 0.23 mmol), (Tetrahedron Lett. 1994, 35, 1545-1548), were heated for 8 hours to give 3-(N-methyl-N-(4-pyridyl)amino)propanol (979 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CBr
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (3.67 g), methyl bromoacetate (0.81 mL), and potassium carbonate (4.66 g) in DMF (21 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered. The solid was combined with the filtrate and washed with water, dried over sodium sulfate and evaporated to give a brown solid which was recrystallized in methanol to give methyl {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetate (2.80 g). 1H-NMR (400 MHz; DMSO-d6): 9.62 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.94-7.85 (m, 2H), 7.63 (d, 1H), 7.17 (s, 1H), 5.04 (s, 2H), 4.00 (s, 3H), 3.72 (s, 3H); MS (EI) for C18H15N3O4Cl2: 408 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31](CO)[CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[CH:41][N:40]=1>O1CCCC1.O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33]([CH:32]=[C:31]([CH2:20][Cl:24])[CH:30]=[C:29]2[O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])=[CH:41][N:40]=2)=[CH:34][CH:35]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CO)cc3ccc(Br)cc23)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CCl)cc3ccc(Br)cc23)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
After a solution of triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrachloride (2 mL) in anhydrous tetrahydrofuran (6 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-methanol (265 mg, 0.63 mmol) was introduced as a solid. The resulting mixture was heated at reflux for 4 hours, cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to afford 2-(7-bromo-3-chloromethyl-naphthalen-1-yloxy)-5-ethanesulfonyl-pyridine (210 mg, 76%) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH2:17][CH3:18])=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[C:19](=O)([O:21]CC)[NH2:20]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][C:5]([CH2:17][CH3:18])=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:20][C:19]1=[O:21]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC)s1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1cc2c(-c3ccccc3Cl)nc(=O)n(C)c2s1
Temperature: 200 °C

Procedure:
A mixture of 11.7 g of 2-methylamino-3-(o-chlorobenzoyl)-5-ethylthiophene, 11.18 g of ethyl carbamate and 0.86 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and contentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-chlorophenyl)-6-ethyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 99°-χ°C (after recrystallization from isopropanol).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>>[CH3:25][O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)N1C1CCNCC1
Reactant: COCc1cccc(C=O)c1
Product: COCc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccc(Cl)cc3)CC2)c1

Procedure:
In similar way as in Preparation example 11, the title compound was prepared from 3-(piperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone and 3-methoxymethylbenzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15]C)=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[C:3]1=[O:20].CO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([OH:15])=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH:17]([CH3:18])[CH3:19])[C:3]1=[O:20]
Reactant: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2c(c1C(=O)O)c(=O)n(C)c(=O)n2C(C)C
Reaction time: 18 h

Procedure:
To a solution of the product of step b) (3.81 g) in THF (50 ml) and methanol (5 ml) was added 1N NaOH (25.7 ml) and the mixture stirred under nitrogen for 18 hr. It was acidified with 2.5N HCl and extracted with DCM, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (3.40 g)
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Br[CH2:6][C:7]([NH:9][C:10]1[C:27]([OH:28])=[C:26]2[C:13]([CH2:14][CH:15]3[C:24]([C:25]2=[O:29])=[C:23]([OH:30])[C:22]2([OH:31])[CH:17]([CH:18]([N:37]([CH3:39])[CH3:38])[C:19]([OH:36])=[C:20]([C:33]([NH2:35])=[O:34])[C:21]2=[O:32])[CH2:16]3)=[C:12]([N:40]([CH3:42])[CH3:41])[CH:11]=1)=[O:8]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:39][N:37]([CH3:38])[C@H:18]1[C@H:17]2[C@:22]([OH:31])([C:23]([OH:30])=[C:24]3[C@H:15]([CH2:16]2)[CH2:14][C:13]2[C:26](=[C:27]([OH:28])[C:10]([NH:9][C:7](=[O:8])[CH2:6][NH:4][O:3][CH3:2])=[CH:11][C:12]=2[N:40]([CH3:41])[CH3:42])[C:25]3=[O:29])[C:21](=[O:32])[C:20]([C:33]([NH2:35])=[O:34])=[C:19]1[OH:36]
Reactant: CON
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CONCC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 21.2 %

Procedure:
The compound of the example is prepared by the procedure of example 1 using 1.5 g of methoxyamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.1 g of the product.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28].CCN(C(C)C)C(C)C>CCO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:24][CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Reactant: NCCC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(NCCC(N)=O)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of the compound of Example 1 Step 4 (2.0 g, 5.5 mmol) in EtOH (50 mL) was treated with 3-amino-propionamide hydrochloride (1.72 g, 13.8 mmol) and DIEA (0.53 g, 27.7 mmol). The resulting mixture was stirred at reflux for 6 h, then cooled to room temperature and concentrated under vacuum. The crude product was dissolved in CH3OH and purified by preparative reverse-phase HPLC (CH3OH/H2O) on a YMC S10 ODS 50×500 mm column to afford the desired product as a yellow glass (0.96 g, 49%); 1H NMR (CD3OD): δ 7.37 (m, 5H), 5.65 (d, J=16.5 Hz, 1H), 5.30 (d, J=16.5 Hz, 1H), 4.70 (t, J=6.0 Hz, 1H), 3.15 (m, 1H), 2.94 (m, 1H), 2.59 (s, 3H), 2.49 (m, 2H), 1.93 (m, 2H), 0.89 (t, J=7.5 Hz, 3H); LC/MS (ESI): 370 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[OH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Reactant: COc1ccccc1[Mg]Br
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3ccccc3OC)cc(OC)c21

Procedure:
The title compound is prepared from 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde (see example 41, step c) and 2-methoxyphenyl-magnesium bromide as described in example 35.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:16][CH2:15]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-formyl-benzenesulfonyl chloride (1.0 g) in DCM (10 mL) was added 4-hydroxypiperidine (0.984 g), followed by NaHCO3 (10 mL, aq sat'd) and the mixture stirred for 2 h at RT. The aqueous layer was washed with DCM (2×25 mL), and the combined organic portions washed with brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide 4-(4-hydroxypiperidine-1-sulfonyl)benzaldehyde. The product was purified on anhydrous silica (10% MeOH/DCM). M+H 269.9
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(C)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.0 g, 12.0 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (23.45 g, 72 mmol) and methyl iodide (17.03 g, 120 mmol) at 0° C. After stirring at room temperature for 3 hours the reaction mixture was cooled to 0° C. and acidified to pH 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane/AcOH=1:1:1) to give the product (1.24 g, 39.1%). 1HNMR (400 MHz, DMSO-d6) δ9.12 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 5.44 (dd, J=9.23, 2.49 Hz, 1H), 3.93-4.08 (m, 2H), 3.73 (s, 3H), 3.08 (dd, J=15.24, 2.64 Hz, 1H), 2.10-2.31 (m, 4H), 1.05-1.19 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C:9]3=[CH:10][C@@H:11]([CH3:24])[C:12]([O:22]C)=[CH:13]4.[NH4+].[OH-]>C(O)(=O)C>[CH3:24][C:11]1[C:12](=[O:22])[CH2:13][C@@:14]23[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:8]([C@@H:9]2[CH:10]=1)[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:16]([OH:17])[C:15]3=1
Reactant: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)C3=C[C@H]1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C=C(C)C(=O)C3

Procedure:
The foam containing (2) was heated at 95° with 90% aqueous acetic acid (500 ml) for 30 minutes. The mixture was cooled in ice and then poured into concentrated NH4OH (1 liter). This basic solution was extracted with three portions of chloroform, the organic extracts backwashed twice with dilute NH4OH, and the organic phase dried and evaporated to a thick syrup. The syrup was fractionated by filtration through a settled slurry of Silica Gel G (400 g), packed in a large sintered glass Buchner funnel using 30:1 methanol-chloroform as the suspending media and eluting solvent. Early fractions contained a mixture of (3a) and the corresponding B/C trans isomer (3b). Later fractions consisting mainly of (3a) were pooled and evaporated to give 94 g of a foam. The foam was crystallized from ethyl acetate to give 31 g (25%) of compound (3a). Recrystallization from ethyl acetate gave white needles of the hemi-ethyl acetate solvate of (3a), m.p. 183°-185.5°. NMR (CDCl3): δ 6.58 (2H), aromatic; 6.40 broad s (2H), H-8 and --OH; 4.30, d (1H), H-5α, J=15 Hz; 3.76, s (3H), CH3O; 2.40, s(3H), CH3N--; 1.60, m (3H), 7 CH3 --.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13])=[O:7].[CH2:26](Br)[CH:27]=[CH2:28]>C1COCC1>[CH2:28]([N:8]([C:6](=[O:7])[C:5]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:4]=1[Br:3])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(OC)ccc2Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(OC)ccc1Br)c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of NaH (680 mg [60% dispersion in oil]) in THF (250 ml) at 0° C. was added methyl 3-[(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate (5.36 g) portionwise. The reaction was stirred for 30 minutes at room temperature when allyl bromide (1.6 ml) was added dropwise and the solution was stirred for a further 20 hours at room temperature. The reaction mixture was quenched with water and then concentrated. The residue was dissolved in ethyl acetate and washed with water (×2), brine, dried (magnesium sulfate) and concentrated. The residue was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to 50% ethyl acetate/iso-hexane to yield methyl 3-[allyl(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate as a colourless oil (4.88 g); Mass Spectrum: M+H+ 417.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:39][CH:40]([F:42])[F:41])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 65 °C
Yield: 95.6 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (450 mg, 0.88 mmol) in THF (8 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (282 mg, 1.32 mmol) in THF (1 mL), followed by DIPEA (250 μL). The resultant reaction mixture was heated at 65° C. for 7 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (485 mg, 96%). 1H NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 2H), 7.78 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 6.13 (tt, J=55.8, 4.3 Hz, 1H), 4.85-4.85 (m, 1H), 3.17-3.12 (m, 2H), 2.75 (td, J=15.7, 4.3 Hz, 2H), 2.37 (t, J=10.9 Hz, 2H), 2.08-2.07 (m, 2H), 1.96-1.95 (m, 2H).