Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[C:4]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.Cl.CCOC(C)=O.[N:24]([O-])=O.[Na+].[CH3:28][O:29][CH2:30][C:31](=[O:37])[CH2:32][C:33]([O:35][CH3:36])=[O:34].CC([O-])=O.[Na+]>CCOC(C)=O.O.CCO>[Br:1][C:2]1[C:3]([F:16])=[C:4]([NH:8][N:24]=[C:32]([C:31](=[O:37])[CH2:30][O:29][CH3:28])[C:33]([O:35][CH3:36])=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCC(=O)C(=NNc1cccc(Br)c1F)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of tert-butyl (3-bromo-2-fluorophenyl)carbamate (7.23 g, 24.9 mmol) in EtOAc (125 mL) was added 4 M HCl/EtOAc (62 mL) at 0° C. The mixture was stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with 6 M HCl aqueous solution (62 mL). To the suspension was added a solution of NaNO2 (2.06 g, 29.9 mmol) in water (5 mL) at 0° C. To a suspension of methyl 4-methoxy-3-oxobutanoate (3.22 mL, 24.9 mmol) and NaOAc (92.9 g) in EtOH (84 mL) was added the above mixture at 0° C. The mixture was stirred at 0° C. for 20 min. The precipitates were collected by filtration, diluted with EtOAc, washed with NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (5.36 g, 62% yield) as a brown solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.30 (3H, s), 3.75-3.94 (3H, m), 4.56-4.71 (2H, m), 7.15-7.34 (1H, m), 7.37-7.59 (1H, m), 7.63-7.80 (1H, m), 12.26 (1H, s).
Reaction SMILES: [C:1]([N:9]1[CH2:16][CH:15]([OH:17])[CH2:14][C@H:10]1[C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(OC(=O)C)(=O)C.[OH-].[Na+].[CH:27](O)(C)C.ClC(=C)[C:33]#[N:34]>>[OH:17][CH:15]1[CH2:16][N:9]2[C:10](=[C:11]([C:33]#[N:34])[CH:27]=[C:1]2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:14]1
Reactant: CC(C)O
Reactant: C=C(Cl)C#N
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(-c2cccnc2)n2c1CC(O)C2
Temperature: 20 °C

Procedure:
A suspension of N-nicotinoyl-4-hydroxyproline (34 g) in a mixture of 2-chloroacrylonitrile (115 cc) and of acetic anhydride (150 cc) is heated at a temperature of about 90° C. for 3 hours and 40 minutes. The solution obtained is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 70° C. The residue obtained is suspended in a 5 N aqueous solution of sodium hydroxide (500 cc) and the resulting suspension is extracted 4 times with ethyl acetate (1,250 cc in total). The organic extracts are combined, washed 4 times with distilled water (1,000 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. A crude product (13 g) is thus obtained, which is dissolved in boiling isopropanol (130 cc). The solution obtained is filtered hot and the filtrate is cooled at a temperature of about 20° C. for 2 hours. The crystals which have appeared are separated off by filtration, washed twice with isopropanol (50 cc in total) and 3 times with diethyl ether (150 cc in total), and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 2-Hydroxy-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine-7-carbonitrile (5.6 g) is thus obtained in the form of beige crystals melting at 190° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]=[C:7]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]3)[N:8]=[CH:9][C:4]=2[CH2:3]1.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[ClH:25].[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]=[C:7]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]3)[N:8]=[CH:9][C:4]=2[CH2:3]1
Reactant: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCc2nc(N3CC[C@@H](N)C3)ncc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
tert-Butyl [(3R)-1-(6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]carbamate (10.0 g, 30.0 mmol) was dissolved in methanol (40 mL) and cooled to 0° C. To this was added a solution of 4 N hydrochloric acid in dioxane (80 mL). The mixture was allowed to warm to room temperature and then stirred at room temperature for 1 hour and then evaporated to dryness. The residue was boiled with ethanol (100 mL) then cooled to 0° C. and the resulting precipitate was filtered off. This gave the title compound (6.99 g, yield 69%) as a pale pink hygroscopic solid. LCMS (ES+) M+H 234. 1H NMR (DMSO-d6) 2.12 (m, 1H) 2.30 (m, 1H) 2.86-2.94 (s+m, 4H) 3.14-3.24 (m, 1H) 3.37-3.46 (m, 1H) 3.56-3.77 (br m, 6H) 3.78 (br m, 1H) 4.13 (dd, J=14.6, 8.3 Hz, 1H) 4.35 (d, J=14.0 Hz, 1H) 8.28 (s, 1H) 8.52 (br s, 3H) 11.71 (br s, 1H). LRMS M+H 234.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CCO>[ClH:19].[C:21]1([CH2:20][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1cccc2ccccc12
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc([C@H]2NC(SCc3cccc4ccccc34)=N[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 1-chloromethylnaphthalene (0.277 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 67 mg of the product 213. 1H NMR (DMSO-d6) δ 11.20 (s, 2 H), 8.40-8.25 (m, 1 H), 8.10-7.90 (m, 2 H), 7.90-7.80 (m, 1 H), 7.80-7.50 (3, H), 7.20-6.70 (m, 10 H), 5.79 (s, 2 H), 4.85 (s, 2 H); MS: m/z 395 (M++1).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][NH:7][CH2:8]2.[OH-].[Na+].C(Cl)(Cl)[Cl:15].[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>O>[ClH:15].[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([N:7]1[CH2:6][CH:5]2[N:4]([CH3:3])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:22])[CH3:19]
Reactant: CN1C2CCC1CNC2
Reactant: ClC(Cl)Cl
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)C(=O)N1CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
8-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (2.5 g, 0.0126 mole) was stirred vigorously in a 2-phase system of 20 ml aqueous 10% sodium hydroxide and 50 ml chloroform for one-half hour at room temperature. Then at 0° C, 2.56 g (0.0189 mole) diethylcarbamyl chloride was added and the reaction was stirred 18 hours at room temperature. Hot water (50 ml) was added. The solution was extracted twice with chloroform and the extract dried with sodium sulfate. After evaporation, a solution of the oily free base in diethyl ether was treated with ethanolic hydrogen chloride to yield 2.92 g (89% yield) 3-(N,N-diethylcarbamyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane monohydrochloride, a white solid melting at 202°-205° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][C@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])[C:24](=[O:25])[NH:26][CH3:27]
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=431.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([O:15][C:16]([C:18]#[C:19][C:20](OCC)=[O:21])=[O:17])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:20](=[O:21])[CH:19]=1)=[O:17])[CH3:14]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)nc2scc(-c3ccccc3)n12
Temperature: 15 °C
Reaction time: 72 h

Procedure:
17.6 g of 2-amino-4-phenylthiazole are dissolved in 100 ml of tetrahydrofuran, the resulting solution is cooled to approximately 15° C. and 17.5 g of acetylene dicarboxylic acid diethyl ester are slowly added to it with stirring at that temperature. The mixture is left standing for 3 days, after which the crystals formed are filtered off the quantity of which was increased by concentrating the mother liquor to approximately half its original volume and recrystallized from ethanol. 3-Phenyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is thus obtained in a yield of 16.9 g, corresponding to 56.3% of the theoretical.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:24][CH:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:25]
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CC(C)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Yield: 23.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-(1-methylethyl)pyrimidine (54.6 mg, 0.349 mmol) and DIPEA (0.122 mL, 0.697 mmol) in N-methyl-2-pyrrolidone (1 mL) were stirred in a microwave reactor at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1) (0.9 mL) and purified by MDAP (2 injections). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (28 mg);
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([N:13]=[C:14]([Cl:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C=CS(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A suspension of N-(4-nitrostyrylsulfonyl)benzamide (14.9 g., 0.045 mole) in 500 ml. of dry benzene is refluxed and stirred with phosphorus pentachloride (10.4 g., 0.05 mole) for 8 hr. The reaction mixture after standing overnight at 25° C. provides 8.2 g. of solid, m.p. 258°-166° C. Concentration of the mother liquor to about 100 ml. provides an additional 2.5 g. of solid, m.p. 158°-161° C. The combined crude solid crystallized from ethyl acetate affords analytically pure N-(4-nitrostyrylsulfonyl)benzimidoyl chloride, m.p. 168°-175° C.
Reaction SMILES: Cl.Cl.N[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=1.CC[N:24](C(C)C)C(C)C.I.[NH2:32][C:33]1[C:34]([C:41]([NH:43][C:44](=[NH:47])SC)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1>C(O)C>[NH2:32][C:33]1[C:34]([C:41]([N:43]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=2)[C:44]([NH2:47])=[NH:24])=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCCNCC(N)=O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: I
Solvent: CCO
Product: N=C(N)N(CCCCc1ccc(OCCNCC(N)=O)cc1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution composed of compound 4 (0.065 g, 0.194 mmol), Hunig's base (0.17 mL, 0.97 mmol) and ethanol (6 mL) was heated at 65° C. for 30 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (5, 0.072 g, 0.213 mmol) was added. The resulting solution was continuously stirred at 65° C. temperature for an additional three hours, then cooled to room temperature. The solvent was then removed by evaporation, and the resulting residue was column chromatographed on silica gel eluting with a mixture of methanol (0-22%), ammonium hydroxide (0-2.2%) and dichloromethane (100-75.8%). This afforded compound 6 (0.078 g, 84%) as a yellow solid. m.p. 92-94° C. (decomposed). 1H NMR (500 MHz, DMSO-d6) δ 1.54 (m, 4H), 2.51 (m, 2H), 2.89 (m, 2H), 3.20 (s, 2H), 3.31 (m, 2H), 4.00 (m, 2H), 6.89 (d, 2H), 7.08 (br, 2H), 7.12 (d, 2H), 7.57 (br, 2H), 9.08 (br, 1H). m/z (ESI) 478.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2c(c1)OCO2
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: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCO5)cc3CC[C@@H]12
Yield: 57.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 130 mg (57%) of the title compound as an amorphous solid. mp 146°-152°. FDMS: m/e=349. α[D]589 =+67.92 (c=1.06, chloroform).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[S:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)c2ccsc2C1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2ccsc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 22) instead of 6-methyl-5,6,7,8-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1.[F:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[Na+].[Na+].CO>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.C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:2]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
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: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)cc12
Temperature: 105 °C
Yield: 124.6 %

Procedure:
A 250 ml pressure flask was loaded with ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.39 g, 3.85 mmol, Example 58C), Pd(Ph3P)4 (280 mg, 0.242 mmol), 2-(3-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.30 g, 5.16 mmol), aqueous Na2CO3 (4.2 ml, 8.40 mmol), MeOH (21.00 ml) and Toluene (42 ml), flushed with nitrogen, sealed and heated to 105° C. for 4 hours in an oil bath. The reaction mixture was filtered and the collected solid washed with water. The filtrate was acidified with KHSO4 (1M solution in water) and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated. The MgSO4 was washed with THF and a MeOH+CH2Cl2 mixture. All wash liquids, the extracted product and the collected solid residue were combined to give 1.95 g crude ethyl 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylate. (estimated purity ˜75%). The crude product was used without further purification in the next reaction. MS (ESI) m/e−405 consistent with [M−H]− of product. HPLC retention time 2.13 min. (PHENOMENEX® Luna C18 S10, 3.0×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc), then isocratic at 100% B.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:20].[C:21]([C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([C:21]#[N:22])[CH:28]=[CH:27][CH:26]=1
Reactant: [Br-]
Reactant: N#Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccccc1
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromide in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:45])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)Cl>[Br:45][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:9]=[N:10][N:11]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a nitrogen-saturated suspension of N-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole (10 g, 20.9 mmol) in DCM was added NBS (3.7 g, 20.9 mmol) and a catalytic amount of benzoyl peroxide (60 mg, 0.2 mmol). The mixture was stirred at reflux for 15 hours. After cooling to room temperature, the precipitate was filtered and the organic solution was concentrated in vacuo. Silica gel chromatography (EtOAc/hexane) gave the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH2:24][NH:25][CH2:26]4)=[CH:21][CH:20]=3)[N:16]=[C:15]([NH2:29])[N:14]=2)[CH2:9][CH2:8]1.[NH2:30][C@@H:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]1[OH:40]>>[NH2:29][C:15]1[N:16]=[C:17]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:1]([NH:30][C@@H:31]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][C@@H:32]4[OH:40])=[O:2])[CH2:26]3)=[CH:21][CH:20]=2)[CH:18]=[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]2)[N:14]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H]3c5ccccc5C[C@@H]3O)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 42 starting from phosgene, 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and (1R,2S)-1-aminoindan-2-ol. Analytic LCMS (M+H)+: m/z=500.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(-c4ccccc4C)c3O2)cc1
Yield: 65.5 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.11 mmol) with 2-methylphenyl boronic acid (1.04 g, 7.66 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.201 g, 0.255 mmol), and potassium carbonate (1.77 g, 12.77 mmol) generally according to the procedure described for Intermediate 37 provided 1.38 g (65%) of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.34 (silica, ethyl acetate:hexanes 1.5:8.5); Anal. calcd. for C23H21FO4S: C, 66.97; H, 5.13. Found: C, 66.95; H, 4.76.