Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:38][C@H:37]3[N:33]([CH2:34][CH2:35][CH2:36]3)[C:32]([CH3:40])([CH3:39])[CH2:31]2)[C:26]([C:41]#[N:42])=[CH:25][N:24]=1.C1(S(O)(=O)=O)C=CC=CC=1>CC(O)C>[CH3:39][C:32]1([CH3:40])[CH2:31][C@H:30]([NH:29][C:27]2[C:26]([C:41]#[N:42])=[CH:25][N:24]=[C:23]([NH:1][C:2]3[CH:7]=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[CH:4][C:3]=3[F:21])[N:28]=2)[CH2:38][C@H:37]2[N:33]1[CH2:34][CH2:35][CH2:36]2
Reactant: Cn1nnn(-c2cc(N)c(F)cc2OCC(C)(C)O)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2OCC(C)(C)O)c1=O
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A mixture of 1-(5-amino-2-(2-hydroxy-2-methylpropoxy)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (305 mg), (7R,8aS)—N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (262 mg), and benzenesulfonic acid (160 mg) in IPA (2 mL) were heated to 80° C. overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-30%) to give desired product (386 mg, 80%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C(O)(=O)C>N>[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Reactant: Nc1ccc(F)cc1F
Agent: N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Temperature: 75 °C
Yield: 87.9 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 4-chloro-6,7-dimethoxycinnoline-3-carboxylate (0.200 g, 0.675 mmol) (Method 7) was added anhydrous ethanol (10 mL), 2,4-difluoroaniline (0.087 g, 0.675 mmol), and glacial acetic acid (˜100 μL). The reaction mixture was then heated to 75° C. for 1 h, cooled to rt, and diluted with concentrated aqueous ammonia (˜5 mL). The crude product precipitated from this reaction mixture and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield the crude product which was purified on 40 g silica using EtOAc as eluent providing 0.231 g (88%) of the title compound as a yellow solid. 1H NMR: 9.25 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.02 (s, 3H), 3.95 (q, 2H), 3.85 (s, 3H), 1.20 (t, 3H); m/z 390.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:21]2[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:14](=[O:24])[C:13]=1[CH3:25].Cl[CH2:27][C@H:28]1[CH2:32][O:31]C(C)(C)[O:29]1>CN(C=O)C>[OH:29][C@H:28]([CH2:32][OH:31])[CH2:27][N:19]1[C:20](=[O:22])[C:21]2[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:13]([CH3:25])[C:14](=[O:24])[N:15]([CH3:23])[C:16]=2[N:17]=[CH:18]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc2n(C)c1=O
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Sodium hydride (67 mg, 3.5 mmol, 5 eq) was stirred in anhydrous DMF (500 μL) for 10 minutes. 5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (300 mg, 0.70 mmol, 1 eq, Example 12) in anhydrous DMF (300 μL) was added and the mixture stirred for 10 minutes. (R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (180 μL, 1.32 mmol, 5 eq) was added and the mixture subjected to microwave irradiation at 135° C. for 1 hour. The solvent was removed in vacuo. The residue was taken up in H2O (1 mL) and THF (1 mL). 1N HCl (1 mL) was added and the solution stirred at RT for 1 hour. After evaporation in vacuo the residue was purified by HPLC to give 88 mg (25%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64 (s, 3H) 2.11 (s, 3H) 3.18 (d, J=5.31 Hz, 1H) 3.32-3.42 (m, 1H) 3.63-3.70 (m, 1H) 3.70-3.82 (m, 1H) 4.24-4.38 (m, 1H) 4.78 (t, J=5.56 Hz, 1H) 5.09 (d, J=5.56 Hz, 1H) 6.62 (t, J=8.72 Hz, 1H) 7.45 (dd, J=7.71, 2.15 Hz, 1H) 7.66 (dd, J=10.61, 2.02 Hz, 1H) 8.48 (s, 1H) 10.16 (s, 1H) [M+H] calc'd for C18H18FIN4O4, 501; found, 501.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 g (0.02 mol) of N-iodosuccinimide and the resulting mixture heated at reflux for 1 h. After cooling to room temperature, the percipitate was removed by flitration and dried under reduced pressure affording 4.6 g (82%) of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][N:4]1[C@H:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:5][N:4]([C@H:12]4[C:20]5[C:15](=[CH:16][C:17]([C:21]6[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[CH2:3]3)[CH2:7][CH2:8]2)=[O:40])=[N:36][CH:37]=1
Reactant: NC(=O)c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Reactant: COc1ccc(CC(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5cnc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyrazine-2-carboxylic acid amide (10-1c, 28 mg, 0.08 mmol) in 3 mL of DMF was added (5-methoxy-pyridin-2-yl)-acetic acid (SM-1aa, 13.0 mg, 0.08 mmol), HBTU (33.0 mg, 0.09 mmol) and triethylamine (0.06 mL, 0.46 mmol). The solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and coevaporated with toluene. The residue was partitioned between 10 mL of dichloromethane and 10 mL of 1N NaOH solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified by Biotage reverse phase column chromatography (Biotage, Inc.) using 100-60% water in acetonitrile to give the desired product 12.0 mg (27%). MS (ES+) 513.4 (M+H)+. 1H NMR (CD3OD) δ 1.56-1.81 (m, 4H), 1.81-2.09 (m, 1H), 2.11-2.35 (m, 1H), 2.93 (d, 1H), 3.12 (d, 1H), 3.20-3.27 (m, 2H), 3.31-3.41 (m, 1H), 3.43-3.66 (m, 4H), 3.69-3.89 (m, 5H), 4.06 (dd, 1H), 4.54-4.81 (m, 2H), 7.25 (d, 1H), 7.34 (dd, 1H), 7.50 (d, 1H), 7.97 (dd, 1H), 8.04 (s, 1H), 8.13 (d, 1H), 9.12 (d, 1H), 9.22 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(COc1ccc(F)cc1)OC
Reaction time: 120 h
Yield: 59.5 %

Procedure:
Dissolve 4-fluorophenol (5.5 g, 49.1 mmol) in acetonitrile (49 mL) and treat the solution with 2-bromo-1,1-dimethoxyethane (11.6 mL, 98.1 mmol) and K2CO3 (16.95 g, 122.7 mmol). Heat the solution to reflux with stirring for five days. Filter the mixture, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to silica gel chromatography eluting with a gradient of 0% to 50% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a colorless oil (5.85 g, 60% yield). Mass spectrum (m/z) 218 (M+NH4)+, 223 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[O:8].[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH2:19])[S:16][N:15]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.CCOC(C)=O>[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH:19][C:7]([NH:6][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:16][N:15]=1
Reactant: Nc1nc(CCl)ns1
Reactant: O=C=NCc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C
Yield: 72 %

Procedure:
3-Fluorobenzyl isocyanate (1.3 g, 8 mmol) was added into a mixture of Intermediate 38: 3-chloromethyl-[1,2,4]thiadiazol-5-ylamine (0.83 g, 5.5 mmol), and DMAP (22 mg, 0.14 mmol) in NMP (11 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 100 C and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (30 mL×2). The aqueous phase was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography to afford 1-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-3-(3-fluoro-benzyl)-urea as an off-white solid (1.2 g, 72%). LC-MS (m/z): 303.0 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:26]=[O:27]
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Yield: 75 %

Procedure:
6-Amino-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (5.00 g, 23 mmol) was suspended in dimethylformamide (77 ml). To the resultant suspension was added phosphorus oxychloride (2.57mL,27.6 mmol), and the resultant mixture was reacted at 60° C. for 3 h. The reaction mixture was diluted with water, and adjusted to ca. pH 12 with sodium hydroxide. The precipitates formed in the reaction mixture was filtered to give a crude product. The crude product was recrystallized from a mixture of ethanol, ethyl acetate and water to give an aldehyde, 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (yield 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.O1CCOCC1>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.O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:25]([C:26]2[S:30][N:29]=[CH:28][N:27]=2)[S:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[C:49]2[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=2)=[N:13][CH:14]=[CH:15]3)(=[O:24])=[O:23])=[CH:33][CH:34]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)nccc3c2)cc1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.157 mmol), potassium carbonate (109 mg, 0.787 mmol), 4-pyridineboronic acid (77 mg, 0.629 mmol), tetrakis(triphenylphosphine)palladium(0) (18.18 mg, 0.016 mmol), dioxane (1049 μl) and water (525 μl). The vial was purged with argon, sealed and heated in a microwave at 100° C. for 35 min. The reaction was cooled to room temperature, diluted with 60 mL of EtOAc, dried over MgSO4, filtered and concentrated. The material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 100% (90:10 MeOH:DCM) in DCM, to provide a yellow glass, N-(4-methoxybenzyl)-1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.158 mmol). This material was carried on to the next step. MS (ESI): 634.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg, 0.42 mmol) in DCM (5 mL) solution were added ethyl 2-aminoacetate (65 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol) and iPr2NEt (0.22 mL, 1.25 mmol). The mixture was stirred at room temperature for 16 hs. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes 20% to 40%) to give ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (240 mg, 100%) as white solid. LC-MS (Condition A), MS m/z 565.1 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].Cl[CH2:14][CH:15]=O.C([O-])(O)=O.[Na+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([CH:14]=[CH:15][N:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccn2ccnc12

Procedure:
A mixture of 2-amino-nicotinic acid ethyl ester (13.845 g), ClCH2CHO (58 mL), and NaHCO3 (11.85 g) was stirred in EtOH (500 mL) at reflux overnight. The reaction mixture was concentrated, diluted with H2O, and extracted with DCM. The product was purified by ISCO using 100% EtOAc first (to remove unreacted starting material), then using 100% DCM to 5% MeOH/DCM. The product eluted at 3% MeOH/DCM, providing imidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester (10.5 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]1([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]1)[C:8](=[O:15])[N:9]2[CH3:14])=O.[C:28]([NH2:31])(=[S:30])[CH3:29]>O1CCOCC1>[CH3:14][N:9]1[C:10]2[C:6](=[C:5]([C:3]3[N:31]=[C:28]([CH3:29])[S:30][CH:2]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]2)[C:8]1=[O:15]
Reactant: CC(N)=S
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)CBr)cccc21
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3C)cs1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
To a suspension of 4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.25 g, 0.57 mmol) in p-dioxane (15 mL) was added thioacetamide (0.047 g, 0.63 mmol) and the reaction mixture, which became homogeneous upon heating, was heated at 80° C. for 1 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in hexanes to afford 1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.076 g, 33%) as an off-white solid: mp 219-220° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.42-7.36 (m, 1H), 7.32-7.27 (m, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.54 (s, 1H), 6.36 (s, 1H), 6.22 (s, 1H), 4.81-4.71 (m, 2H), 4.21-4.07 (m, 4H), 3.29 (s, 3H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.4, 165.2, 156.1, 151.8, 144.4, 137.7, 133.2, 129.2, 128.6, 124.7, 122.2, 116.6, 111.2, 108.2, 99.1, 78.3, 77.4, 64.7, 64.0, 58.8, 27.0, 19.1; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)(=[O:6])[CH2:4][CH3:5].O>C(Cl)(Cl)Cl>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1)=[O:6]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cn1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Bromine (0.52 ml.) in chloroform (50 ml.) was added to solution of 2-propionyl 5-trifluoromethylpyridine (2.03 g.) in chloroform (20 ml.) over 1 hour under photoflood illumination. After addition was complete the reaction was stirred for 16 hours at room temperature. The reaction was then poured into water, and the organic phase was separated, washed with water, dried over magnesium sulphate and concentrated to dryness to give 2-(2-bromopropionyl)-5-trifluoromethylpyridine as an oil which was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:14][CH2:13][CH2:12][O:11]3)O1.Br[C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([NH2:28])=[C:21]([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:11][CH2:12][CH2:13][O:14]3)[CH:26]=1
Reactant: CC1(C)OB(C2=CCCCC23OCCO3)OC1(C)C
Reactant: Nc1nnc(Cl)cc1Br
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(Cl)cc1C1=CCCCC12OCCO2
Yield: 42.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using the 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene (0.64 g, 2.40 mmol) prepared in Example 82a, 4-bromo-6-chloropyridazin-3-amine (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (275.7 mg, 43%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: Cc1cccc(Br)n1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cccc(C)n3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (79 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 11) (324 mg, 0.69 mmol), 2-bromo-6-methylpyridine (118 mg, 0.69 mmol) and hexamethylditin (225 mg, 0.69 mmol) in 1,4-dioxane (15 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2cc(C(=O)O)oc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cccc(C)c2o1

Procedure:
A solution of 4.32 g of 7-methylbenzofuran-2-carboxylic acid in 150 ml of methanol and 1 ml of conc. H2SO4 is stirred at reflux over 9 hours. The reaction mixture is cooled and concentrated by evaporation. The residue is dissolved in diethyl ether and washed with water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a red-brown oil from the residue. Rf=0.32 (1:6 EtOAc-heptane); Rt=4.51.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:43]([C:45]([C:48]([F:51])([F:50])[F:49])([F:47])[F:46])=[O:44])[CH:40]([CH3:42])[CH3:41].Cl>C(Cl)Cl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:38][C@H:39]([C:43]([C:45]([C:48]([F:49])([F:50])[F:51])([F:46])[F:47])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Dissolve Boc-Val-Pro-OH (314 mg, 1.0 mmol) in methylene chloride (4 mL) and add N-methylmorpholine (252 mg, 2.5 mmol). Cool to -22° C. and add isobutylchloroformate (136 mg, 1.0 mmol). Stir for 20 minutes and add to H-Val-CF2CF3.hydrochloride (1.1 mmol). Stir for 1 hour at -22° C., allow to warm to room temperature and stir for 3 hours. Purify by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (405 mg).