Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[OH:7][C:8]1[C:9]([CH3:43])=[C:10]([CH:36]=[CH:37][C:38]=1[C:39](=[O:42])[CH2:40][CH3:41])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)C(O)=O)=[CH:15][CH:14]=1.[N+](=C)=[N-]>O1CCCC1.CN(C)C=O>[Cl:6][CH2:1][C:2]([C:22]1[CH:21]=[C:20]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]3[CH:36]=[CH:37][C:38]([C:39](=[O:42])[CH2:40][CH3:41])=[C:8]([OH:7])[C:9]=3[CH3:43])=[CH:18][CH:17]=2)[CH:28]=[CH:27][CH:26]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Agent: C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Add oxalyl chloride (0.660 mg, 5.20 mmol) to a solution of 3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid (2.50 g, 5.00 mmol) in tetrahydrofuran (0.20M). Add dimethylformamide (5 drops). Add ethereal solution of diazomethane (15.0 mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) to quench unreacted diazomethane and evaporate solvents to afford the title compound (2.25 g, 4.19 mmol, 85%): MS (m/z): 536 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of N,N-dimethylethylenediamine (1.46 g, 0.0166 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanolisopropyl ether-tetrahydrofuran to give 4.45 g (73%) of white flakes, mp 195°-197° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9](=O)[CH:10]([CH3:12])[CH3:11])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].C(O)(=O)C.[NH2:18][C:19]([NH2:21])=[NH:20]>CN(C)C=O>[C:1]([O:4][C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:18][C:19]([NH2:21])=[N:20][C:6]=1[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(C)=O)C(=O)C(C)C
Reactant: N=C(N)N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)nc(N)nc1C(C)C
Temperature: 100 °C
Yield: 30.1 %

Procedure:
A mixture of 3-acetoxy-5-methyl-2,4-hexanedione (5 g, 27 mmol) and guanidine acetate (6.4 g, 54 mmol) in 100 ml dimethylformamide (DMF) was heated at 100° C. for 3 hours. After cooling, the concentrated reaction was filtered through a pad of silica gel using an eluent consisting of equal volume parts of hexane and ethylacetate. The filtrate was concentrated and the residue was treated with excess acetic anhydride in the presence of triethylamine. The reaction mixture was concentrated and the residue was crystallized from boiling hexane to yield 1.7 g (31%) 5-acetoxy-2-amino4-isopropyl-6-methylpyrimidine, m.p. 141°-142° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: Clc1cnccc1CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cc(C(F)(F)F)nc(SCc2ccncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3-chloropyridine hydrobromide (7.2 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (922 mg, 4.7 mmol) in absolute ethanol (40 mL) was added triethylamine (4.0 mL, 28.7 mmol). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. Diethyl ether (2×50 mL) was used to wash the recovered solid. The solid material was removed by filtration. The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×25 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×30 mL), diethyl ether (1×30 mL), and hexanes (2×30 mL), and was dried in vacuo to afford 2-{[(3-chloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (822 mg, 54%); 1H NMR (500 MHz, DMSO-d6): δ 4.50 (s, 2H), 6.66 (s, 1H), 7.58 (d, 1H, J=4.9 Hz), 8.47 (d, 1H, J=4.9 Hz), 8.64 (s, 1H); M+ 322.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C@:13]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:12][CH2:11][N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[C:33](=[O:35])[NH:17]1)[CH:15]=[CH2:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC[C@@](N)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reaction time: 3 h
Yield: 20.3 %

Procedure:
To a solution of (R)—N1—((S)-1-(4-bromophenyl)ethyl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (12 g, 31 mmol) in CH2Cl2 (100 mL) and Et3N (36 g, 0.36 mmol) was added triphosgene (3.50 g, 11.8 mmol) at 0° C. The resulting mixture was stirred for 3 h. The mixture was washed with water. The organic layer was separated, and concentrated to give the crude product, which was purified by column chromatography to afford (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (1.0 g, 8%). 1H NMR (CDCl3): δ=1.49 (t, 3H), 2.00 (m, 2H), 2.35 (m, 2H), 2.76 (m, 2H), 5.18 (m, 2H), 5.31 (m, 2H), 5.72 (q, 1H), 6.95 (m, 4H), 7.18 (m, 2H), 7.254 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:27][NH2:28].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:27][NH:28][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNCc1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 0.08 h

Procedure:
Mix propane-2-sulfonic acid [2-(4′-formyl-biphenyl-4-yl)-thiophen-3-yl]-amide (0.16 mmol) in 1,2-dichloroethane (2 ml) and add methylamine 2N in THF (0.16 ml, 0.32 mmol) at room temperature. Stir the resulting solution for 5 min before adding Na(OAc)3BH (0.32 mmol). Stir the mixture at room temperature for 16 h. Analyze by LC/MS for final product. Add saturated NaHCO3 aqueous solution and dichloromethane and filter the mixture through hydrophobic filter. Evaporate the filtrate and apply the residue to SCX cartridge, elute with MeOH/DCM to remove non-basic materials, followed by 2N NH3 in MeOH to give a crude product. Purify by flash chromatography (Silica gel-Dichloromethane/Methanol 7:1)to yield the title compound. MS (ES−): 399(M−1).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:36][CH2:35][C:12]4[N:13]=[C:14]([C:24]5[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]6[C:25]=5[C:26]([CH3:34])=[N:27][NH:28]6)[N:15]=[C:16]([N:17]5[CH2:20][CH:19]([O:21][CH2:22][CH3:23])[CH2:18]5)[C:11]=4[CH2:10]3)[N:6]([CH3:37])[N:5]=2)[CH2:3][CH2:2]1.[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:38][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([CH3:37])[C:7]=1[N:9]1[CH2:36][CH2:35][C:12]2[N:13]=[C:14]([C:24]3[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[C:25]=3[C:26]([CH3:34])=[N:27][NH:28]4)[N:15]=[C:16]([N:17]3[CH2:18][CH:19]([O:21][CH2:22][CH3:23])[CH2:20]3)[C:11]=2[CH2:10]1
Reactant: CCOC1CN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2cc(C4CC4)nn2C)CC3)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC1CN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)C1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-4-(3-ethoxyazetidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (30 mg, 0.060 mmol) in DCM (2 mL) was added N-chlorosuccinimide (9.64 mg, 0.072 mmol) at room temperature. The mixture was stirred for 30 min then concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile-H2O with 0.1% NH4OH) to give 6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-4-(3-ethoxyazetidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.43 (d, J=8.46 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 4.49 (dd, J=6.63, 9.41 Hz, 2H), 4.35-4.45 (m, 3H), 4.14 (dd, J=4.04, 10.36 Hz, 2H), 3.66 (s, 3H), 3.46-3.55 (m, 4H), 2.89 (t, J=5.68 Hz, 2H), 2.27 (s, 3H), 2.04 (s, 3H), 1.81-1.88 (m, 1H), 1.19 (t, J=7.01 Hz, 3H), 0.76-0.93 (m, 4H); MS (ESI+) m/z 533.4 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12](N)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)C.N([O-])=O.[Na+].[F:21][B-](F)(F)F.[H+]>>[F:21][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([OH:4])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: COc1c(N)cc(C(=O)O)cc1OC(C)=O
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: COc1c(O)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of step 1 (2.0 g, 8.88 mmol) was dissolved in aqueous tetrafluoroboric acid (48%, 4.5 ml), sodium nitrite (612 mg, 8.88 mmol) was added at 0° C., and the mixture was stirred at room temperature for 60 min. The volatiles were evaporated, toluene was added to the oily residue and the mixture was heated at 100° C. for 4 h. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 170 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][C:15]2[CH:19]=[C:18]([N:20]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[N:22]=[CH:21]3)[S:17][C:16]=2[C:29]([O:31][CH3:32])=[O:30])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example B14, 110.5 mg of 4-fluoro-2-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:9][C:4]1[C:3]([CH2:2][C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1ncccc1CCl
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncccc1CC#N
Temperature: 45 °C
Reaction time: 8 h

Procedure:
970 mg (6.85 mmol) of the compound from Example 37A are initially introduced into 10 ml DMF, 336 mg (6.85 mmol) sodium cyanide are added and the mixture is stirred overnight at 45° C. The reaction mixture is introduced on to 75 ml saturated ammonium chloride solution and extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography on silica gel (mobile phase: methylene chloride/methanol 20:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C@H:9]([OH:11])[CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][S:23]([O:11][C@H:9]([CH3:10])[CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:12])(=[O:25])=[O:24]
Reactant: Cc1ccc(F)cc1C[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (6.1 g, 36.3 mmol) and DIEA (12.6 mL, 72.6 mmol) in 200 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (3.4 mL, 43.5 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (30 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4, concentrated, passed through silicagel pad to give crude (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (F-2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[C:21]([Si:18]([O:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=1[Cl:1])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(F)(F)F)c1Cl
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a solution of 2-chloro-3-trifluoromethyl-phenol (509 mg, 2.59 mmol) in CH2Cl2 (20 mL) was added imidazole (264 mg, 3.88 mmol). The mixture was stirred for 5 minutes, to which was added portionwise tert-butyldimethylsilyl chloride (467 g, 3.1 mmol). The mixture was stirred for 2 hours at room temperature and was diluted with EtOAc. The crude mixture was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl-(2-chloro-3-trifluoromethyl-phenoxy)-dimethyl-silane (800 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(P([CH:24]2[CH2:29][CH2:28]CCC2)C2CCCCC2)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>O.C1(C)C=CC=CC=1>[CH:28]1([C:2]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:29][CH2:24]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: N#Cc1ccc(F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)C1CC1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1C1CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
500 mg commercially available 2-Bromo-4-fluorobenzonitrile, 70 mg tricyclohexylphosphine, 2.04 g tri potassium phosphate mono hydrate and 278 mg cyclopropylboronic acid placed in a reaction vessel and 11 ml toluene were added. The mixture was degassed with argon, then 561 mg palladium(II)acetate were added and the reaction mixture stirred at 100° C. for 1.5 hours. To the cooled reaction mixture was added 30 ml water and the mixture was extracted five times with portions of 30 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=5:1 to obtain 310 mg 2-Cyclopropyl-4-fluoro-benzonitrile as yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.N1C=CC(B(O)O)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[Cl:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:3]3[CH:2]=[CH:6][S:5][CH:4]=3)[C:8]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:9]=3[C:10]=2[CH:11]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2-c2cscc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2-c2ccsc2)C1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-pyridinylboronic acid (48.5 mg, 0.394 mmol) and K3PO4 (139.39 mg, 0.657 mmol) in DMF-water (2:0.2 mL) was added dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 8-chloro-2-methyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). 1H NMR (TFA salt, CD3OD) δ (ppm): 7.7 (dd, 1H), 7.58 (m, 2H), 7.2 (m, 3H), 4.76 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH:20]1[CH2:23][NH:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:21][CH:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: c1ccc(OC2CNC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 2,5-dichloronicotinate (217 mg, 1.05 mmol) in tetrahydrofuran (5 ml), 3-phenoxyazetidine (D48) (149 mg, 1.05 mmol) and triethylamine (117 mg, 1.16 mmol) were added and the mixture was heated at reflux for 18 hours. The resulting mixture was cooled to room temperature, the precipitates were filtered off and the filtrate was concentrated under vacuo. The residue was dissolved in ethyl acetate (5 ml), washed with water (5 ml) and brine (5 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1. Collected fractions after solvent evaporation afforded the title compound (D75) (250 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5](=O)[C:3]1=[O:4].NN.[Na].O>C(O)C>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Agent: NN
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CN1C(=O)Cc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Yield: 87 %

Procedure:
1-Methyl-4,6-dichloroisatin (4.0 g) was suspended in dry ethanol (40 ml), hydrazine (9 ml) was added and the mixture was refluxed in 6 h. The mixture was then added slowly at 70° C. to a solution of sodium (1.74 g)in dry ethanol (80 ml) and refluxed overnight. The reaction mixture was cooled to room temperature, water (50 ml) was added and the volume was reduced to about one third by evaporation. The mixture was then poured onto icewater (1000 ml) and acidified with 6M HCl (pH=1). The precipitate was filtered off washed with water and dried to afford 3.27 g (87%) of (43). M.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(C(C)C)CC)C.[CH2:28]([O:30][C:31]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34])[CH3:29].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:33]([C:32]3[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:31]=3[O:30][CH2:28][CH3:29])=[O:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN(CC)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)n1cc(-c2ccc(OC)c(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1(250 mg, 0.98 mmole) was dissolved in 50 mL of CH2Cl2. N,N-diethylisopropylamine (205 uL, 1.2 mmol), 2-ethoxy-4-nitro-benzoic acid (228 mg, 1.1 mmol) and bromotris(pyrolodino)phoshonium hexafluorophosphate (550 mg, 1.1 mmol) were added to the stirring reaction mixture. The mixture was stirred at ambient temperature for 4 h and washed consecutively with saturated sodium bicarbonate and saturated potassium bisulfate solution. The resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield 340 mg (77%) of the titled compound as a yellow solid. MS(ESI) [M+H+]+=448.2.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CCO>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:11])[CH2:12][N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(NCC2CO2)n1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: OC(CNc1cccc(Br)n1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred mixture of 6-bromo-N-(oxiran-2-ylmethyl)pyridin-2-amine (1.33 g, 5.81 mmol) in EtOH (100 mL) was added 1,2,3,4-tetrahydroisoquinoline (773 mg, 5.81 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated and the residue was purified column to afford the desired compound (140 mg). LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5]CCC1.[Br:7][CH:8]([CH:11]=[O:12])[CH:9]=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[Br:7][C:8](=[CH:11][O:12][CH:6]([CH3:5])[CH3:1])[CH:9]=[O:10]
Reactant: C1CCCCC1
Reactant: O=CC(Br)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC=C(Br)C=O
Temperature: 25 °C
Yield: 103 %

Procedure:
With moderate agitation, a 20 gallon reactor system was charged with cyclohexane (29.12 L), 2-bromo-malonaldehyde (2.33 kg), p-toluenesulfonic acid monohydrate 43.94 g, and 2-propanol (4.65 L). The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.). A total of 16 L of distillate was removed from the reaction via the cooling tower. This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor. The reaction solution was cooled to near ambient temperature and transferred to a 10 gallon reactor system at 40° C. An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.). The mobile dark orange oil was drained from the vessel and transferred to a rotary evaporator receiver flask and further concentrated under house vacuum at ~30° C. using a rotary evaporator. About 0.2 L more of solvent was removed. Total product obtained was 3.072 kg (16 mol, 103% yield). The product was used as obtained in the next step. This material is unstable and must be kept in a freezer (<-5° C., under nitrogen). The shelve-life is about 2 weeks.