Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.21-1.34, 2.57, 2.73, 2.82, 3.00, 3.79, 4.41, 5.76, 6.82, 7.17; HRMS (FAB) calcd for C20H26BrN3O+H 404.1338, found 404.1317. Anal. Calcd for C20H26BrN3O: C, 59.41; H, 6.48; N, 10.39; Br, 19.76. Found: C, 59.05; H, 6.42; N, 10.13.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][CH:8]1[S:12](=[O:14])(=[O:13])[O:11][CH2:10][CH2:9]1>O1CCCC1>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:6][CH2:10][CH2:9][CH:8]([S:12]([OH:14])(=[O:13])=[O:11])[CH3:7]
Reactant: CC1CCOS1(=O)=O
Reactant: CC(C)CCN
Solvent: C1CCOC1
Product: CC(C)CCNCCC(C)S(=O)(=O)O
Temperature: 25 °C
Yield: 28 %

Procedure:
To a hot solution of isoamylamine (2.0 g, 22.9 mmol) in tetrahydrofuran (THF, 11 mL) was added via syringe pump (2 hour addition) a solution of 2,4-butane sultone (3.1 g, 21.8 mmol in THF (total of 5 mL)). The solution was stirred at reflux for an additional 2 hours. The reaction was cooled to room temperature. The solid was recovered by filtration and it was washed with THF (25 mL) and acetone (25 mL). The solid was dissolved in water (20 mL) and Dowex 50×8 (10 g) was suspended in the solution. The mixture was stirred for 15 minutes and the resin was filtered. The solvent was evaporated under reduced pressure. Yield: 28%. 1H NMR (H2O, 500 MHz) δ ppm 3.07 (t, 2H, J=7.8 Hz), 2.92 (t, 2H, J=7.8 Hz), 2.87 (m, 1H), 2.06 (m, 1H), 1.77 (m, 1H), 1.51 (m, 1H), 1.42 (m, 2H), 1.18 (d, 3H, J=6.8 Hz), 0.78 (d, 3H, J=6.3 Hz). 13C(H2O, 125 MHz) δ ppm 53.21, 46.32, 45.37, 34.36, 28.16, 25.35, 21.51, 14.79. ES-MS 224 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 3.11 g (9.72 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 10 ml of ethanol, 2 ml of water and 400 mg of sodium hydroxide is heated to boiling under reflux for 1 hour. After evaporation of the ethanol, the residue is treated with 10 ml of 1 N hydrochloric acid. The colourless material obtained is filtered off under suction, washed with water and dried. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid with a decomposition point of 283°-284°.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:10][C:5]2[N:6]([C:2]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:3][N:4]=2)[N:7]=1
Reactant: NC1CCCCC1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Product: Clc1ccc(-c2cc3nnc(NC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (38 mg, 0.1 mmol) in cyclohexylamine (0.5 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL), washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (40-100%) in hexanes to afford 18 mg (41%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=3.58 min, (M+H)+=438.1. 1H NMR (CDCl3, 400 MHz): δ 7.87 (s, 1H), 7.35-7.43 (m, 3H), 7.30-7.33 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.31Hz, 2H), 4.83 (s, 1H), 3.98 (s, 1H), 2.22-2.25 (m, 2H), 1.79 (dd, J=9.78, 3.67 Hz, 2H), 1.63-1.72 (m, 1H), 1.41-1.52 (m, 2H), 1.27-1.39 (m, 2H), 1.21-1.26 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[P:29]([O-:33])([O-:32])([O-:31])=[O:30]
Reactant: O=P(O)(O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of phosphoric acid (0.29 ml) in 2-propanol (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1>CC(O)=O.CCO.O>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][N:19]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][NH2:1])[CH:15]=[CH:16][CH:17]=1
Reactant: NNc1cccc(Cl)c1
Reactant: NCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NCC(=NNc1cccc(Cl)c1)c1ccccc1
Yield: 86.1 %

Procedure:
A mixture of 3.12 g 2-aminoacetophenone and 3.29 g 3-chlorophenylhydrazine in 4 ml HOAc and 20 ml EtOH was refluxed for one hour. The cooled reaction mixture was diluted with water and the precipitate was collected, washed with water, and dried to give 5.16 g solid. Recrystallization from methanol gave 2.12 g solid, m.p. 131°-134° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[O:4][CH2:3]1.[C:20]([O:24][C:25]([NH:27][C@:28]([CH3:34])([CH2:32][CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:34][C@:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21])([C:29](=[O:30])[NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:11][CH:2]([CH3:1])[CH2:3][O:4]3)=[CH:14][CH:15]=1)[CH2:32][CH3:33]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1COc2cccc(Oc3ccc(N)cn3)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Temperature: 25 °C
Yield: 401.6 %

Procedure:
In a 8 mL 6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinamine (Intermediate 119, 82.4 mg, 0.0305 mmol), (2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid (59.7 mg, 0.275 mmol) and DIPEA (0.080 mL, 0.458 mmol) were dissolved in N,N-Dimethylformamide (DMF) (2 mL) to give a pale yellow solution. HATU (151 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature over week-end. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (55.8 mg) as white solid.
Reaction SMILES: C=C1OC(=O)C1.[OH:7][C:8]1[CH:17]=[C:16]([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cu]>[CH3:18][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8](=[O:7])[CH:17]=1
Reactant: Cc1cc(O)nc2ccccc12
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: C=C1CC(=O)O1
Agent: O=C([O-])[O-]
Product: Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 54.7 %

Procedure:
The synthetic precursor (1) is prepared either by an Ullmann coupling according to a literature procedure (Wawzonek, et al., J. HETEROCYCLIC CHEM., 25, 381 (1988)) or via the reaction of the corresponding diarylamine with diketene followed by acid cyclization (Elderfield, HETEROCYCLIC COMPOUNDS, Vol. 4, pp. 1-331, (1952)). Thus 10.0 g (62.9 mmoles) of 2-hydroxy-4-methylquinoline is heated at reflux with 24.0 g (377 mmoles) of copper powder, 8.68 g (62.9 mmoles) of potassium carbonate and 19.2 g (94 mmoles) of iodobenzene for 48 hours. The reaction is cooled to room temperature, partitioned between water and ethyl acetate, filtered, and the organic layer is dried over magnesium sulfate. The crude product is purified on a silica gel column, eluting with 1:1 ethyl acetate/hexanes to yield 8.1 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:20])[CH2:17][S:18][CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C(=O)(O)[O-]>C(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16](=[O:20])[CH2:17][S:18]([CH3:19])=[O:29])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CS(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.75 h

Procedure:
1-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(methylsulfanyl)ethanone (15.00 g, 50.94 mmol) is dissolved in CH2Cl2 (100 mL) in a flame-dried flask under argon then cooled in an ice/H2O bath. mCPBA (85%, 10.45 g, 51.47 mmol) is added carefully, generating some gas evolution of H2. The reaction is stirred for 1.75 h while maintaining the bath temperature until the last 20 minutes when the bath is allowed to warm. The reaction is then poured into saturated bicarbonate, separated and extracted with 2× CH2Cl2. The organics are concentrated on a rotavap then dried under vacuum (being careful of foaming). This gives a light tan foam which is purified by flash chromatography on silica with 1.6 L 27.5% acetone in hexanes then 100% acetone. A white solid is obtained which can be crystallized with EtOAc/hexanes with refrigeration to give white crystals, mp=143.6°-144.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)(=[O:31])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:15]([O:39][CH3:40])[CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)(=[O:30])=[O:31])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:15]([O:39][CH3:40])[CH:14]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: COc1ccccc1B(O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ccc(-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)c(OC)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 23.9 %

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.008 g, 0.012 mmol), 2-methoxyphenylboronic acid (0.036 g, 0.234 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From example 160; 0.050 g, 0.117 mmol), potassium phosphate (0.099 g, 0.469 mmol), 1.5 mL dioxane, and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product, so the aqueous layer was removed and the reaction mixture was treated with HCl (4N in dioxane) (117 μl, 0.469 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. The crude residue was purified by [PREP LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min10-40%_LV_NH3] yielding 1-(2′,3-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.014 g, 0.028 mmol, 24.0%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.67 (s, 3H) 3.79-3.88 (m, 3H) 6.99-7.13 (m, 2H) 7.17 (d, J=8.12 Hz, 1H) 7.22-7.32 (m, 2H) 7.32-7.48 (m, 3H) 7.81 (d, J=8.76 Hz, 1H) 7.98 (d, J=9.03 Hz, 1H) 8.09 (d, J=5.61 Hz, 1H) 8.26 (br. s., 1H) 8.58 (s, 1H) 8.61-8.72 (m, 2H); (M+H)+=499.3.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:21]([O-])=O)=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[H][H]>[Ni].CO>[NH2:21][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:24]=[CH:25][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: [H][H]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(C(=O)OC)c2)cc1
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2ccc(N)c(C(=O)OC)c2)cc1
Yield: 41.4 %

Procedure:
0.7 g of Raney nickel was added to a methanol (150 ml) solution of 6.98 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-nitrobenzoate, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 2.65 g of the entitled compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39]1([NH2:42])[CH2:41][CH2:40]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:42][CH:39]3[CH2:41][CH2:40]3)=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: NC1CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NC3CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 47.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.2 g, 0.36 mmol), cyclopropylamine (0.05 g, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.18 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.36 g, 3.6 mmol) was added to the solution at room temperature. The reaction mixture was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopropylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 15a (0.1 g, yield 45%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-6-nitrobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-methyl-6-nitrobenzoate with m.p. 44–45° (Chem. Pharm. Bull., Vol. 29, 1475 (1981)). Methyl 2-methyl-6-nitrobenzoate is hydrogenated in methanol in the presence of palladium, 10% on carbon powder, at room temperature and atmospheric pressure to give methyl 2-methyl-6-aminobenzoate.
Reaction SMILES: ClCCl.C(=O)([O-])[O-].[K+].[K+].Br[C:11]1[N:16]=[C:15]([C:17](=[O:20])[NH:18][CH3:19])[C:14]([NH:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:46][CH3:47])[N:23]=2)=[CH:13][CH:12]=1.[CH2:48]([O:55][CH2:56][CH2:57][CH2:58][N:59]1[CH:63]=[C:62](B2OC(C)(C)C(C)(C)O2)[CH:61]=[C:60]1[C:73]([O:75][CH3:76])=[O:74])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:48]([O:55][CH2:56][CH2:57][CH2:58][N:59]1[CH:63]=[C:62]([C:11]2[CH:12]=[CH:13][C:14]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([CH2:37][P:38]([O:39][CH2:40][CH3:41])([OH:42])=[O:43])=[CH:35][C:34]=4[O:46][CH3:47])[N:23]=3)=[C:15]([C:17](=[O:20])[NH:18][CH3:19])[N:16]=2)[CH:61]=[C:60]1[C:73]([O:75][CH3:76])=[O:74])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1CCCOCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cc(C(=O)OC)n(CCCOCc5ccccc5)c4)nc3C(=O)NC)n2)c(OC)c1
Yield: 82.3 %

Procedure:
A mixture of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (77.9 mg, 0.095 mmol), potassium carbonate (366 mg, 2.65 mmol), ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 543 mg, 0.877 mmol) and methyl 1-[3-(benzyloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound 38E, 385 mg, 0.964 mmol) in 4:1 dioxane:H2O (3.8 mL) was degassed with Argon and irradiated for 30 min at 100° C. in a CEM microwave reactor. The reaction was then concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [5→100% MeOH in Water] to afford 586 mg of the title compound (82%). MS (ESI): m/z 812.60 [M+H]+. UPLC: tR=1.57 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@@H:19]3[CH2:23]B(C(OC(C)(C)C)=O)[C@@H:21](C(OC)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[Cl-].[NH4+:37]>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:20][C@H:21]([C:5]([OH:35])([CH3:6])[CH3:4])[NH:37][CH2:23]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CB1C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CN1
Reaction time: 1 h
Yield: 31 %

Procedure:
A Grignard solution of MeMgl (0.270 mL, 3M in diethyl ether, 0.810 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)borolane-1,2-dicarboxylate (0.039 g, 0.081 mmol, prepared as described in Synthesis 89-A) in THF (1 mL) and the solution refluxed for 10 h. Saturated aqueous ammonium chloride (20 mL) was added and the aqueous phase extracted with ethyl acetate (3×20 mL). Organic phases were combined, dried (MgSO4) and concentrated. The resulting crude Boc-protected amine was stirred with 4M HCl in dioxane (6 mL) for 1 h. The mixture was concentrated and the crude purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography (3 cm plug of silica), eluting with 20% methanol in dichloromethane, gave the title compound as a solid (0.012 g, 31%).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=2)[NH2:15])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].O>C(Cl)Cl>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH:15][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 5 h
Yield: 91.4 %

Procedure:
A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline (0.5 g, 1.93 mmol) and pyridine (0.31 mL, 3.80 mmol) in CH2Cl2 was treated dropwise with ethylsulfonyl chloride (0.27 mL, 2.89 mmol). The mixture was stirred for 5 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (3/1) as the eluting solvent gave N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamide as a yellow oil (0.62 g).
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[C:10]([CH2:27][CH3:28])=[N:11][N:12]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=2[F:26])[C:13]=1[CH2:14][CH3:15])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][N:40]=1.C(O)(=O)C>CN(C)C=O>[CH2:27]([C:10]1[C:9]([CH2:8][C:6]([OH:5])=[O:7])=[C:13]([CH2:14][CH3:15])[N:12]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]3[NH:38][C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:44]4[N:45]=3)=[CH:19][C:18]=2[F:26])[N:11]=1)[CH3:28]
Reactant: Nc1cccnc1N
Reactant: CCc1nn(Cc2ccc(C(=O)O)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3nc4cccnc4[nH]3)cc2F)c(CC)c1CC(=O)O
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To a stirred solution of 4-(4-tert-butoxycarbonylmethyl-3,5-diethylpyrazol-1-ylmethyl)-3-fluorobenzoic acid (19 mg) in dimethylformamide (2 ml) at room temperature is added diisopropylethylamine (50 μl). After 10 min, the solution is added to 2,3-diaminopyridine (7 mg). After 2 days, glacial acetic acid (2 ml) is added and the reaction is heated to 130° C. After 15 h, the reaction is allowed to cool to room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane and trifluoroacetic acid (200 μl) and water (200 μl) are added. After 15 h, the reaction mixture is concentrated in vacuo. The residue is purified by HPLC to yield (3,5-diethyl-1-[2-fluoro-4-(3H-imidazo[4,5-b]pyridin-2-yl)benzyl]-1H-pyrazol-4-yl)acetic acid (10 mg; [M+H]=429; HPLC retention time 1.34 min (Method A)).