Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-]#N.[K+].[CH3:16][N:17](C=O)C>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:16]#[N:17])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 42.5 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45° C. for 45 minutes and was stirred at room temperature for 18 h. The reaction was heated at 40° C. for 24 h, was cooled to room temperature, and additional potassium cyanide (1.02 g, 15.71 mmol) was added. The reaction was heated at 40° C. for 18 h and was cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3×25 mL). The combined organic layers were washed with 1N LiCl followed by brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 3-cyanomethyl-benzoic Acid methyl ester (1.36 g). MS 193 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][OH:24].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][OH:24])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: OCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 30 °C

Procedure:
Levorotatory (−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (50 gm), 2-chloroethanol (31.4 gm), potassium iodide (1.3 gm) and sodium carbonate (40.8 gm) are taken in toluene (446 ml) and refluxed for 24 hours. The reaction mixture is cooled to 25-35° C., washed with water (285 ml) followed by two times with water (each time 185 ml). The layers are separated. Toluene is evaporated from organic layer under reduced pressure to yield 58 gm of levorotatory (−)-[2-[4-[(4-Chlorophenyl)-phenylmethyl]-1-piperazinyl]ethanol.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@:16]12[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:55])[CH3:54])=[C:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C=O.[BH3-][C:59]#N.[Na+]>CO>[C:1]([O:4][C@@H:5]([C@:16]12[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:55])[CH3:54])=[C:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:45])([CH3:46])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH3:59])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](CNCc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H](CN(C)Cc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192 mmol) in MeOH (6 mL) stirred in air at rt was added formaldehyde (31.2 mg, 0.384 mmol). The reaction mixture was stirred at rt for 2 h. Then it was added NaCNBH3 (85 mg, 1.345 mmol) portionwise and stirred for overnight. The solvent was evaporated and the residue diluted with DCM and washed with water and brine. The dried organics were filtered and concentrated to give 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (68) (120 mg, 65% yield) as a white solid. This material was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.31-7.26 (m, 2H), 7.24-7.16 (m, 2H), 5.65 (d, J=8.5 Hz, 1H), 4.50 (br. s., 1H), 3.66-3.51 (m, 1H), 3.49-3.36 (m, 1H), 3.27-3.06 (m, 2H), 2.73-2.32 (m, 5H), 2.26 (s, 3H), 2.08-0.73 (m, 49H); LC/MS: m/z calculated 793.5. found 794.3 (M+1)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.O>CN(C)C=O>[C:22]([NH:26][C:27]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and tert-butylisocyanate (0.19 mL, 1.60 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.45 mL, 3.20 mmol) at room temperature under nitrogen. After 18 h, water (200 mL) was added and the product was extracted with CH2Cl2 (5×100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 1-tert-butyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.24 g, 40% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 7.51 min (98.18%); mp: 260-262° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H, 3 CH3), 1.89-2.11 (m, 1H, CHH), 2.28-2.48 (m, 1H, CHH), 2.60 (d, J=17.6 Hz, 1H, CHH), 2.80-3.04 (m, 1H, CHH), 4.17-4.36 (m, 3H, CHH, CH2), 4.44 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.78 (s, 1H, Ar), 6.20 (t, J=5.9 Hz, 1H, NH), 7.37 (d, J=7.9 Hz, 1H, Ar), 7.44 (s, 1H, NH), 7.67 (d, J=7.7 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 29.30, 31.21, 42.58, 47.10, 49.11, 51.56, 121.73, 122.87, 126.75, 130.14, 142.32, 145.55, 157.28, 167.98, 171.00, 172.85; LCMS: MH=373; Anal Calcd for C19H24N4O4: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.00; H, 6.57; N, 15.03.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.C(Cl)Cl.O.[Cl-].[Na+].O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28)(3 g, 14.1 mmol) and potassium carbonate (2.92 g, 21.1 mmol) in DMF (30 ml) was stirred under nitrogen at ambient temperature for 5 min. To the pale yellow suspension was added 1-(bromomethyl)-4-chloro-2-(trifluoromethyl)benzene (3.85 g, 14.07 mmol, Alfa Aesar). The mixture turned to a colourless suspension. The reaction mixture was stirred at ambient temperature under nitrogen overnight. The reaction mixture was diluted with DCM (50 ml) and water (50 ml). To the emulsion was added brine (30 ml). The resulting phases were separated and the aqueous layer further extracted with DCM (50 ml). The combined organic extracts were filtered through a hydrophobic frit and the solvent removed in vacuo to give 2-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (6.14 g) as an off-white gum.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32])[CH3:21].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:27][C:26]=1[F:32])[CH3:21]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.104 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) the title compound was obtained (0.14 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(OCC)(=O)C>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CO[C@H](Cc1ccc(N)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@H](Cc1ccc(NC(C)=O)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To (R)-(−)-3-(4-aminophenyl)-2-methoxypropionic acid (40 g) in a 0.5 L glass reactor was added ethyl acetate (80 g) and acetic anhydride (62.8 g). The mixture was stirred at 90° C. for 1 hour. Upon cooling, the solvent was removed by vacuum distillation, providing an oily residue. To this residue was added water (120 g) and ethyl acetate (120 g). After stirring for 10 min at 35° C., the layers were separated and the aqueous layer discarded. The organic layer solvent was removed by vacuum distillation. Acetone (120 g) was then added and the resulting mixture was warmed until dissolution was complete. The solution was cooled to 0° C., and the product precipitated which was collected by filtration. The solid was rinsed with acetone (20 g) and dried at 65° C. to afford 26 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C1COCC1>[OH:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:24](=[O:23])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1

Procedure:
(S)-3-Amino-4-(4-(trifluoromethyl)phenyl)butan-1-ol was dissolved in 5 mL THF and 4 mL K2CO3 (1M, aq.) and BOC2O were added. The reaction was stirred over night and acidified (about pH 2). The reaction was extracted with EtOAc (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as a white solid and used without further purification. LCMS (API-ES) m/z (%): 333.1 (100%, M++H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[CH:4][N:5]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Product: Clc1cc(N2CCCCC2)ncn1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 10.0 g (67.1 mmol) of 4,6-dichloropyrimidine and 5.7 g (67.1 mmol) of piperidine in 100 ml of water is stirred at a bath temperature of 115° C. for 16 h. After cooling to RT, the precipitate is filtered off, washed with water and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(F)cc3)nn3ccnc23)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.15 mmol), 4-fluorophenylboronic acid (0.025 g, 0.18 mmol), Pd(dba)2 (0.02 g, 0.035 mmol), X-Phos (0.02 g, 0.042 mmol) and Na2CO3 (0.032 g, 0.3 mmol) in dioxane/H2O (20 mL/2 mL) was stirred at 95° C. for 18 h under N2 atmosphere. The solvent was removed in vacuo and the residue purified by chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to give 6-(4-fluorophenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.025 g, 43%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.85 (s, 1H), 8.03-7.98 (m, 3H), 7.63 (s, 1H), 7.48 (t, 1H, J=7.9 Hz), 7.30-7.24 (m, 2H), 6.34 (d, 1H, J=7.8 Hz), 6.13 (d, 1H, J=8.1 Hz), 4.30 (brs, 1H), 3.65-3.33 (m, 2H), 2.18-2.05 (m, 3H), 1.81 (brs, 1H), 1.24 (d, 3H, J=6.0 Hz) LC/MS: 389 [M+H]+, tR=2.03 min. HPLC: 95.87% at 214 nm, 99.64% at 254 nm, tR=4.79 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([CH3:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=2[N:24]=1>CN(C=O)C>[Cl:18][C:19]1[N:20]=[C:21]([O:1][CH2:2][C@H:3]2[C@H:7]([CH3:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4]2)[C:22]2[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=2[N:24]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of tert-butyl trans-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (0.58 g, 2.7 mmol) in DMF (15 mL) was added NaH (60% in oil, 162 mg, 4.05 mmol) at 0° C. After stirring at rt for 30 min, 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.85 g, 2.7 mmol) was added to the mixture. The resulting mixture was stirred at rt for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The reaction mixture was quenched by water (10 mL) and extracted with EtOAc (two×20 mL). The combined organic layers were washed with brine (four×20 mL), dried over Na2SO4 and concentrated to yield the title compound (1.34 g, 100% yield) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][CH:32]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH2:25][CH2:24][O:23][CH3:22])[CH:28]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1
Yield: 24.8 %

Procedure:
This compound was prepared in similar fashion to the method outlined for Example 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (456 mg, 1.15 mmol) was reacted with 2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example 5 step 5, 392 mg, 1.50 mmol) to afford title compound (120 mg, 25%) as a colourless powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30]O.CN(C=O)C>ClCCl>[Cl:3][CH2:30][C:7]1[N:8]=[CH:9][N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of thionyl chloride (1.3 ml) in dry dichloromethane (10 ml) was added over 5 min to a stirred suspension of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-methanol (5.0 g) in a mixture of dichloromethane (100 ml) and dry DMF (2 ml) at 0°. The mixture was stirred at 0° for 0.5 h and washed consecutively with 8% sodium bicarbonate (2×50 ml), water (50 ml), dried and evaporated in vacuo below 40° to give an oil (5 g). This was dissolved in ether (100 ml) and the resulting solution filtered through a pad of silica which was further eluted with ether (2×100 ml). The combined filtrates were evaporated below 40° to give a white foam which was triturated with cold hexane and filtered to give the title compound (4.2 g) as a white crystalline solid, m.p. 133°-135°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13]C(=O)N)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(#[N:28])C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>O>[NH2:28][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]([OH:19])=[O:18]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC#N
Agent: O=Ic1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(benzyloxycarbonyl)-L-asparagine (7.5 g) were added ethyl acetate (36 ml), acetonitrile (36 ml), water (18 ml) and iodosobenzene diacetate (10 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the obtained solid was washed with ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[NH4+].[OH-].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1N
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1,2-diaminobenzene (5.00 g, 46.3 mmol) in acetic anhydride (36.5 mL) was heated for 17 hours at 90° C. and then stirred for 17 hours at ambient temperature. The reaction mixture was taken to pH 9 by dropwise addition of NH4OH, with ice added as necessary to keep the mixture cool, followed by cooling in an ice bath. The resulting precipitate was filtered, rinsed with H2O, and dried in a vacuum oven to give 5.28 g of 2-methylbenzimidazole as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2].C1COCC1.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (960 mg) were added THF (19.2 ml), methanol (9.6 ml) and 1N sodium hydroxide (3.4 ml), and the mixture was stirred at room temperature for 3 hours. Under reduced pressure, the organic solvent was evaporated. To the residue was added ethyl acetate, and the mixture was extracted with water. To the mixture was added 6N hydrochloric acid (2 ml), and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic acid (850 mg).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26](=O)[CH2:27][CH2:28][CH3:29]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:26]([CH3:25])[CH2:27][CH2:28][CH3:29])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CCCC(C)=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CCCC(C)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with pentan-2-one (0.9 g, 10.4 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:26]([O:28][CH3:29])=[O:27])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)(=O)C.Cl>CO>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][N:12]1[C:13]2[C:9](=[C:8]([OH:7])[CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc2c(OC(C)=O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
Sodium methoxide (92 mg) was added to methyl 4-acetoxy-N-(3,4-dichlorobenzyl)indole-2-carboxylate in methanol (10 ml) and the reaction stirred for 4 hours. The reaction was then acidified with 2 M HCl to precipitate a white solid which was filtered and dried in vacuo (0.21 g, 77%); NMR δ (CD3SOCD3) 3.80 (s, 3H), 5.74 (s, 2H), 6.45 (d, 1H), 6.75-6.82 (m, 1H), 6.95 (d, 1H), 7.04-7.15 (m, 2H), 7.30 (m, 1H), 7.41 (s, 1H), 9.89 (s, 1H); M/z (+) 318 (MH+).