Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[H][H]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(-c2cccs2)cc1N
Yield: 89.5 %

Procedure:
To a solution of 4-thienyl-2-nitroaniline (1 equiv, 400 mg, 1.82 mmol) was added 10% Pd/C (0.05 equiv, 97 mg, 0.09 mmol). The resulting suspension was stirred for overnight over 1 atm of hydrogen. The solids were filtered through celite pad and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography with gradient of MeOH (0-10%) in CH2Cl2 to afford compound 30 (310 mg, 90%) and a white solid. LRMS (ESI): (calc) 190.2 (found) 191.0 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].N1([C:48]([NH:50][CH2:51][C:52]2[CH:67]=[CH:66][C:55]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])=[CH:54][CH:53]=2)=[O:49])C=CN=C1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48]([NH:50][CH2:51][C:52]3[CH:67]=[CH:66][C:55]([C:56]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[O:57])=[CH:54][CH:53]=3)=[O:49])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(OCc1ccccc1)c1ccc(CNC(=O)n2ccnc2)cc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)OCc5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purin-2-carboxamide (Preparation 10) and benzyl 4-{[(1H-imidazol-1 ylcarbonyl)amino]methyl}benzoate (Preparation 54) by a similar method to Example 1. The target compound was obtained as a white solid.
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C(=O)(O)[O-].[Na+]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([Cl:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[C:21]([F:24])=[CH:20][N:19]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 50 °C
Yield: 101.7 %

Procedure:
Trimethylsilyl bromide (1.8 mL, 13.2 mmol) was added to a suspension of 3-chloro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (1.43 g, 4.40 mmol) in propionitrile (40 mL) at room temperature, under argon. The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was adjusted to pH 7 by careful addition of a saturated aqueous solution of sodium bicarbonate. The resultant mixture was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (1.65 g, 100% yield). 1H NMR (300 MHz, CDCl3): δ 8.42 (d, J=1.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([CH3:13])=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(Cl)cc1

Procedure:
A solution of 70 g (0.54 mol) of 4-chloroaniline, 70 ml (0.54 mol) of ethyl acetoacetate, and 0.6 ml acetic acid in 400 ml toluene was heated in a Dean-Stark apparatus for 19 at 130° C. The mixture was evaporated, and the remaining crystalline precipitate stirred with diisopropylether and filtered. The filtrate was concentrated and the residue purified via column chromatography on silica gel with dichloromethane/hexane 4:1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.[CH:18](=[O:22])[CH:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC(C)C=O
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.7 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (2.03 g, 8.93 mmol) in dry THF (10 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 13.4 mmol, 8.38 mL). The mixture was stirred for 5 minutes then isobutyraldehyde (1.22 mL, 8.38 mmol) was added and the mixture was slowly warmed up to room temperature and stirred overnight at room temperature. Aqueous ammonium chloride was added and the solution extracted with ethylacetate and the organic extract was dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (0% to 20% ethyl acetate in hexane) to give 1.97 g of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-ol (100%). 1H NMR (300 MHz; CDCl3): δ 0.77 (d, J=6.6 Hz, 3 H), 0.90 (d, J=6.6 Hz, 3 H), 1.33 (s, 6 H), 1.95 (m, 1 H), 4.23 (s, 2 H), 4.28 (d, J=7.2 Hz, 2 H), 6.72 (d, J=8.4 Hz, 1 H), 7.03 (dd, J=8.1 Hz and 1.8 Hz, 1 H), 7.06 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Br[C:19]1[S:20][C:21]([CH3:24])=[N:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[S:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (Compound 1B, 600 mg, 1.916 mmol) and 2-bromo-5-methyl-1,3,4-thiadiazole (480 mg, 2.68 mmol) in DMF (15 mL) was added potassium carbonate (794 mg, 5.75 mmol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 100% EtOAc) to afford 6-bromo-2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazole (455 mg, 1.106 mmol, 58% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.78 (1H, d, J=1.9 Hz), 7.50-7.56 (1H, m), 7.45-7.50 (1H, m), 5.40-5.52 (1H, m), 3.77-3.88 (2H, m), 3.54-3.66 (2H, m), 2.61 (3H, s), 2.19-2.29 (2H, m), 2.07-2.17 (2H, m). LCMS (m/z)=412 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:29][NH:30][C:31]1[S:32][C:33]([S:37]([NH2:40])(=[O:39])=[O:38])=[C:34]([CH3:36])[N:35]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:40][S:37]([C:33]1[S:32][C:31]([N:30]([CH3:29])[C:15](=[O:17])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)=[N:35][C:34]=1[CH3:36])(=[O:38])=[O:39]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2ccccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.33 g (73.3 mmol) of (2′-fluoro[1,1′-biphenyl]-4-yl)acetic acid and 9.9 g (73.3 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 600 ml of dimethylformamide at room temperature. 16.84 g (81.4 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 15.58 g (81.4 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The dimethylformamide is substantially removed at 50° C. under high vacuum, and the residue is taken up in 400 ml of dichloromethane and then washed with 350 ml of each of water and 10% citric acid solution. Drying over magnesium sulfate and removal of the solvent in vacuo results in the compound of Example 57 in the form of a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]1([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:34][C:30]([C:32]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:33]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:31]
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CC(O)(c1ccccc1)c1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-phenylbut-3-yn-2-ol. MS (+ESI) m/z: 417.1.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S([N:21]2[C:29]3[C:24](=[C:25]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=O)=O)=CC=1>C(O)C.C(OCC)(=O)C>[CH:2]1([NH:1][CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH:23]=[CH:22][NH:21]3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Reactant: NC1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(CNC1CCCc2ccccc21)COc1cccc2[nH]ccc12
Yield: 12.8 %

Procedure:
A mixture of 1-aminotetralin (5.15 g) and 1-[1-(p-toluenesulfonyl)indol-4-yloxy]-2,3-epoxypropane (12 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is then evaporated off and the oily residue is dissolved in absolute ethanol (100 ml). A solution of sodium hydroxide (7.5 g) in water (30 ml) is added thereto. The obtained reaction mixture is refluxed for 6 hours and then evaporated under reduced pressure. The residue which is obtained is then dissolved in ethyl acetate (150 ml), the organic solution is thoroughly washed with water, dried over sodium sulfate, and filtered. Ethyl acetate is then evaporated off and the obtained oily residue is chromatographed on a silica gel column eluting with a mixture ethyl acetate/cyclohexane 7/3 v/v. The combined fractions are evaporated to dryness, the oily residue is taken up in a very small amount of ethyl ether which is then removed under vacuum yielding 1.5 g of N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(4-indolyloxy)propanamine, as a vitreous solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])=[O:7])([CH3:4])[CH3:3].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH3:33])=[O:25]>CN(C)C=O.ClCCl>[C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[S:16][C:23]([C:24](=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH3:33])=[CH:18][N:17]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CCc1ccccc1C(=O)CBr
Reactant: CN(C)C=NC(=S)NC[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccccc1C(=O)c1cnc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.1 %

Procedure:
To a solution of 2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester (150 mg) in N,N-dimethylformamide (2 ml) was added 2-bromo-1-(2-ethylphenyl)-ethanone (109 mg). The mixture was stirred 65 h at room temperature, diluted with dichloromethane, washed twice with water, once with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (2:1 ethyl acetate/hexane eluant) to afford the product as yellow oil (129 mg, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[C:13]([C:29]#[N:30])[C:12](=O)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:12]1[C:13]([C:29]#[N:30])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[N:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(-c2ccc([N+](=O)[O-])cc2)cc1=O
Product: N#Cc1c(Cl)cc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 95 °C
Yield: 61.9 %

Procedure:
A mixture of 6-(4-nitrophenyl)-4-oxo-2-(4-phenoxyphenyl)-1,4-dihydropyridine-3-carbonitrile (211 mg, 0.515 mmol) and phosphoryl trichloride (1 mL, 10.92 mmol) was heated to 95° C. for 30 min, then concentrated. The residue was dissolved in dichloromethane (2 mL) and washed with saturated sodium bicarbonate. Silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, gave 4-chloro-6-(4-nitrophenyl)-2-(4-phenoxyphenyl)nicotinonitrile as white solid (136.3 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.35-8.41 (2H, m), 8.27-8.33 (2H, m), 8.00-8.06 (2H, m), 7.91 (1H, s), 7.38-7.46 (2H, m), 7.21 (1H, t, J=7.40 Hz), 7.10-7.18 (4H, m); MS (ES+) m/z: 428 (M+14); LC retention time: 4.141 min (analytical HPLC Method A).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>O>[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[S:1]([Cl:14])(=[O:3])=[O:2])#[N:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: O
Product: N#Cc1ccccc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 91.5 %

Procedure:
44 grams(0.24 mole) of saccharin and 100 grams(0.48 mole) of phosphorus pentachloride were stirred at 110° C. to 120° C. for 3.5 hours. The reaction mixture was then poured into 500 milliliters of ice and water, stirred until solidified, filtered, ground with water, re-filtered, and dried to give 44.3 grams of 2-cyanobenzenesulfonyl chloride and pseudosaccharin chloride. Based on saccharin, the per cent yield was 92.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:34][NH:35]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5)c[nH]4)C3)nc(N)n2)cc1F
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of 4-{2-amino-6-[2-(4-phenyl-1H-imidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (310 mg, 0.702 mmol) and hydrazine (2.5 mL, 79 mmol) in ethanol (4 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated to afford the crude title compound (400 mg) as a yellow solid. This material was combined with another batch of crude title compound (100 mg). The combined material was washed with CH2Cl2 (2×8 mL) and dried in vacuo. The resulting residue was purified by Prep-HPLC using CH3CN in water (0.5% ammonium hydrogen carbonate in water) from 25% to 30% to afford the title compound (220 mg) as a yellow solid. LC-MS (ES) m/z=454 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.08-3.14 (m, 1H), 3.18-3.24 (m, 1H), 3.72 (m, 1H), 4.04-4.07 (m, 1H), 4.30-4.34 (m, 1H), 4.59-4.64 (m, 1H), 4.73-4.75 (m, 1H), 5.39 (s, 2H), 6.21 (s, 2H), 6.71 (s, 1H), 7.16-7.20 (m, 1H), 7.31-7.36 (m, 2H), 7.61-7.63 (m, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.78 (d, J=7.2 Hz, 2H), 7.99 (s, 1H), 11.53 (s, 1H), 12.33-12.62 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:14]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:11])[F:12])[N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(C(F)(F)F)n1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 42.2 %

Procedure:
A mixture of 11.0 g of 2-isopropenyl-6-trifluoromethylpyridine, 8.7 g of N-chlorosuccinimide and 25 ml of benzene was stirred at 80° C. for 7 hours. After the reaction mixture was cooled to room temperature, 50 ml of n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane-ethyl acetate 20:1) to obtain 5.5 g of the objective compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[C:42]([C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:42]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[C:3]([NH:5][C@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:4])=[O:51])=[CH:53][CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Prepared using General Procedure 7. A stirred solution of (R)-tert-butyl 2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate (122 mg, 0.218 mmol), 4-(tert-butyl)benzoic acid (38.8 mg, 0.218 mmol) and TEA (60.7 μl, 0.435 mmol) in DMF (4 mL) was cooled to 0° C. and HATU (87 mg, 0.228 mmol) was slowly added over 5 minutes. The reaction was stirred at room temperature for 2 h, then diluted with EA (100 mL), washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The solvent was dried over MgSO4 and removed. The crude product was purified by chromatography 0-30% ACN in DCM to afford 123 mg (78%) of (R)-tert-butyl 2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate as a white solid. LCMS-ESI (m/z) calculated for C44H56N4O5: 720.4; no m/z observed, tR=3.47 min (Method 11).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:22]([O:29][C:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)C(Cl)(Cl)Cl)c1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The mixture of methyl 3-(2-trichloroacetylpyrrol-1-yl)benzoate (10.0 g), benzyl alcohol (3.3 ml) and potassium carbonate (4.4 g) in N,N-dimethylformamide (30 ml) was stirred for 6 hours at ambient temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with toluene. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoate (8.35 g) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[C:8]([CH3:22])=[C:9]([S:12]([N:15]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1[CH3:11])=[O:5])C>C1COCC1.O>[Cl:34][C:31]1[S:30][C:29]([C:27]2[O:26][N:25]=[C:24]([CH2:23][N:7]3[C:8]([CH3:22])=[C:9]([S:12]([N:15]4[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)(=[O:14])=[O:13])[C:10]([CH3:11])=[C:6]3[C:4]([OH:5])=[O:3])[CH:28]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1c(C)c(S(=O)(=O)N2CCCOCC2)c(C)n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)N2CCCOCC2)c(C)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of [5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg) in 20 mL of THF/water(3:1) was added LiOH monohydrate (200 mg) The mixture was stirred for 2h at 45° C. and for 6 h at 60° C. whereupon it was cooled to RT, concentrated, acidified with 2M HCl to pH=2 and extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated to give crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid (80 mg) which was used directly in the next step.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccsc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1sccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile as described in Example 65 to give 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]thiophene-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 7.32 (1H, d, J 7), 7.44-7.47 (2H, m), 7.63-7.66 (1H, m), 7.72 (1H, d, J 5), 7.88 (1H, dd, J 7 and 2), 8.12 (1H, s), 9.09 (1H, d, J 7).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][CH2:12][CH2:13][OH:14]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:14][CH2:13][CH2:12][F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCCF
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1OCCF

Procedure:
From intermediate 21 and 2-fluoroethanol, reacted in an analogous manner to the preparation of intermediate 89. (UPLC-MS 6) tR 0.50; ESI-MS 182.0 [M+H]+.