Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]1[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)c1ccco1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccccc2C)o1
Yield: 33.5 %

Procedure:
A mixture of 2-methylbenzyl bromide [prepared as described by Radziszewaki and Wispek, Ber, 15, 1747 (1882); 18.5 g.], methyl 2-furoate (15.3 g.) and anhydrous ferric chloride (0.3 g.) in dry carbon tetrachloride (25 ml.) was heated on a steam bath under reflux for 18 hours and then distilled to give crude methyl 5-(2-methylbenzyl)-2-furoate (7.7 g.) in the form of a pale brown coloured oil, b.p. 120°-145° C./0.1 mm.Hg, suitable for use as a starting material in procedures hereinafter described.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]#[CH:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:15][C:14]#[CH:13]
Reactant: COC(=O)c1ccc(F)c(O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(C(=O)OC)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 4-fluoro-3-hydroxybenzoate (20.0 mL, 0.118 mol) was dissolved in anhydrous acetone (450 mL), mixed with propargyl bromide (26.2 g, 0.177 mol) followed by the addition of powdered K2CO3 (32.4 g, 0.236 mol) and the reaction mixture was stirred overnight at room temperature. The reaction was filtered and the solvent was removed in vacuo. The residue was dissolved in diethyl ether, washed 4 times with H2O, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 25.5 g (100% yield) of a light peach coloured solid as the title compound (mp 60.5-61.5° C.). Mass spectrum (70 eV) m/z (relative intensity) 208 (27, M+), 207 (100), 193 (22), 177 (20), 149 (50), 82 (21), 81 (10).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8](Cl)(=[O:10])=[O:9])[C:4]([CH3:12])=[N:3]1.[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH2:36])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][C:30]4[S:31][C:32]([CH2:35][NH:36][S:8]([C:5]5[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])(=[O:10])=[O:9])=[CH:33][N:34]=4)[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1S(=O)(=O)NCc1cnc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)s1
Temperature: 40 °C

Procedure:
33 mg of 1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride (0.16 mmol, 1.2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40° C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered, and submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[C:16]([O:23][CH3:24])[N:15]=2)[CH:3]=1.[NH3:25].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[C:16]([O:23][CH3:24])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C(C)C)c(OC)n1
Reactant: N
Solvent: CO
Product: COc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1C(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (500 mg, 1.43 mmol) was added 7N ammonia in MeOH (20.5 mL, 143 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(5-isopropyl-6-methoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (450 mg, 98%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) 8 ppm 11.47 (s, 1H), 9.10 (s, 1H), 8.17 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 5.71 (s, 1H), 4.04 (s, 3H), 3.18 (m, 1H), 1.23 (d, J=7.1 Hz, 6H).
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH:2]1C(O)=O.OS(O)(=O)=O.[N-:23]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[NH2:23][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:14]([CH2:13][CH2:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:1]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C1CCC2c3ccccc3CCC2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: NC1CCC2c3ccccc3CCC2C1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a mixture of 11.7 g (0.05 mole) of 1,2,3,4,4a,9,10,-10a-octahydrophenanthrene-2-carboxylic acid, 80 ml of conc. H2SO4 and 200 ml of CHCl3 is added with stirring at 50°-60° 3.64 g of sodium azide in small portions. After completed addition, heating at 50° is continued for 1 hr longer, the the mixture poured onto ice and then rendered alkaline with caustic. The product is extracted into CHCl3, dried and freed of solvent to give about 9 g of 2-amino-1,2,3,4,4a,-9,10,10a-octahydrophenanthrene, which is subjected to a Birch reduction as per Example 1E and then reacted with hydrogen peroxide in the presence of formic acid as per Example 1F to form the title compound.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8])[CH3:2].[CH2:12]=O>C(O)=O>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: COc1cccc(CCN)c1
Reactant: C=O
Solvent: O=CO
Product: COc1ccc2c(c1)CCNC2
Reaction time: 24 h

Procedure:
To the solution of 3-methoxylphenethylamine (15.1 g, 0.1 mol) in formic acid (100 ml) at rt is added paraformaldehyde (3.0 g, 0.1 mol, 1.0 eq.). The resulting mixture is stirred at 40˜50° C. for 24 hr. After the reaction is completed, the formic acid is evaporated and the residue is diluted with water (200 ml), basified with sodium hydroxide solution (10.0N, 10.5 ml) to pH=10, and extracted with EtOAc. The combined organic layers are washed with water and brine and dried over sodium sulfate, and the solvent is removed under reduced pressure to give the title compound. MS (+VE) m/z 164.1 (M++1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:91])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:91])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(C)cc1-c1cccc-3c1
Product: Cc1cc2c(cc1C)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Yield: 61 %

Procedure:
Prepared in 61% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,18,22,28-pentamethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.39 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 5.79 (br. s., 1H), 4.60 (d, J=4.8 Hz, 1H), 4.02-3.86 (m, 2H), 3.51 (br. s., 1H), 3.36 (br. s., 1H), 2.55 (s, 1H), 2.43 (br. s., 3H), 2.36 (br. s., 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.00-1.52 (m, 10H), 1.20 (br. s., 3H), 1.17 (s, 9H), 1.03 (d, J=5.5 Hz, 3H); LCMS (ESI, M): 687.3.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methoxy-benzoyl chloride (34.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (12.5 mg, 0.0323 mmol, 16.2%). ESI-MS m/z calc. 386.1. found 387.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:12]3[N:13]=[C:14]([SH:16])[S:15][C:11]=3[CH2:10][C:9]=2[CH:8]=1)C.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:16][C:14]2[S:15][C:11]3[CH2:10][C:9]4[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])[CH:19]=[CH:18][C:17]=4[C:12]=3[N:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc2c(c1)Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1ccc2c(c1)Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 42 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize-the title compound. Yield 42%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([CH2:19]O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C(Cl)Cl>[Br:22][CH2:19][CH:11]1[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1
Reactant: OCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of compound 11 (1.25 g, 4.07 mmol) and CBr4 (2.33 G, 7.04 mmol) in CH2Cl2 (15 ml) was added Ph3P (1.82 g, 6.92 mmol) in CH2Cl2 (15 ml) at 0° C. The reaction was allowed to warm to room temperature overnight, was then poured into water ((40 ml), extracted with CH2Cl2 (75 ml), dried over Na2SO4, and the solvent was evaporated. The residue was purified by chromatography, CombiFlash silica gel column, EtOAC hexanes, EtOAc from 0% to 15%, to give compound 12 as a clear oil (mixture of cis and trans diastereomers, 1.50 g, 99%). 1H NMR. (CDCl3) δ 1.52-1.62 (m) and 1.97-2.15 (m, total 2H), 2.25-2.30 (m, 1H), 2.64-2.77 (m, 1H), 3.02-3.12 (m, 1H), 3.34-3.47 (m, 2H), 4.08 (dd, J=12 Hz, 5.2 Hz) and 4.26 (t, J=3.6 Hz, total 1H), 6.72-7.39 (m, 7H). 13C NMR (CDCl3) δ 31.8, 34.6, 35.6, 36.8, 37.2, 39.2, 39.3, 39.4, 43.3, 46.4, 126.5, 126.8, 126.9, 127.2, 128.3, 128.4, 128.6, 129.0, 129.4, 129.5, 129.7, 130.2, 130.5, 130.7, 130.9, 132.5, 132.8, 136.1, 136.3, 138.3, 147.0, 147.5.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:40]([O:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:38])([F:37])[F:39])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])=[CH:15][CH:14]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])[CH2:51][CH2:52]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 748.41 (100) [MH+]; HPLC: tR=0.85 min (UPLC, purity).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH2:43][CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH2:43][CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (332 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][CH:28]=1>C1COCC1>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a flask charged with N-(4-methoxybenzyl)thiazol-2-amine (180 mg, 0.816 mmol) was added THF (3 ml) and the resulting mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide (1M in THF) (855 μl, 0.855 mmol). The resulting light brown solution was stirred for 15 min at 0° C. prior to the addition of a solution of perfluorophenyl 4-bromoisoquinoline-7-sulfonate (353 mg, 0.777 mmol) in THF (2 ml), followed by 1 ml THF wash. The resulting solution was allowed to stir and warm slowly to room temperature (ice melt). After 2 hr LC/MS indicated about 70% conversion fairly cleanly, with starting amine and PFP ester present (no change from 1 hr). The solution was cooled back to 0° C. and 0.5 eq LiHMDS (1 M) was added. After 1 hr LC/MS indicated complete consumption of starting material. To the mixture was added 400 μl acetic acid and the mixture was dried under reduced pressure and purified with a 40 g HP Silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 50%, 10% DCM throughout) affording product as a white solid 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (202 mg, 0.412 mmol, 53.0% yield). m/z (ESI) 490.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].O.O.O.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17]>CCOC(C)=O>[CH2:1]([NH:5][C:6]1[S:7][C:8]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCCNc1nccs1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to the mixture of 2-butylaminothiazole (1 g 6.41 mmol) prepared above and hexafluoroacetone trihydrate (2.86 g 13 mmol). The mixture was heated to gently reflux at 100° C. overnight. EtOAc is added and the mixture was filtered. Solvent was evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title compound as a white solid. (1.68 g). 1H NMR δ0.95 (t, 3H), 1.40 (m, 2H), 1.6 (m, 2H), 3.20 (t, 2H), 7.3 (s, 1H); ESIMS: m/z 323 (M+H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)([OH:3])=[O:2].Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:2][C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)=[O:3])[CH3:25]
Reactant: COc1cc(OCC(=O)O)ccc1-c1nc2ncccc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)COc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1
Reaction time: 8 h

Procedure:
1 g of 2-(4-carboxymethoxy-2-methoxyphenyl)imidazo(4,5-b) pyridine is dissolved in 20 ml of ethanol, the solution is saturated with HCl gas and allowed to stand overnight. After concentration and the usual work-up, 2-(4-ethoxycarbonylmethoxy-2-methoxyphenyl)imidazo(4,5-b)pyridine is obtained; hemifumarate, m.p. 198°.
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[CH:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C1([NH2:19])CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:14]1[C@@H:15]([NH2:19])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: O=C1CCC(CO)(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyridin-2-yl)cyclohexanone (410 mg, 2.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) was treated at 0° C. with cyclopropylamine (280 uL, 4.0 mmol, 2 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed (brine), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 5% MeOH/CH2Cl2 containing 2.5% NH4OH) to provide the trans amine. Further elution afforded the cis amine.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[O:12][N:11]=2)C=CC=CC=1.[N-]=C=O.[NH2:23][C:24]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=2)[CH2:28][N:27]=[C:26]2[O:37][CH:38]=[CH:39][C:25]=12>>[NH2:23][C:24]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:8]([NH:9][C:10]3[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[O:12][N:11]=3)=[O:19])[CH:31]=2)[CH2:28][N:27]=[C:26]2[O:37][CH:38]=[CH:39][C:25]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: [N-]=C=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(N3CN=c4occc4=C3N)c2)no1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using (5-t-butyl-isoxazol-3-yl)-carbamic acid phenyl ester as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 393 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[CH3:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH3:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-dimethylpropanoyl chloride (20 mg, 164 mmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.9 mg, 81% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]2[NH:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][NH:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(C2CNCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
1.54 g of 4-Bromobenzyl bromide and 1 g of 3-Phenylpiperazine in 20 mL of acetonitrile were stirred at room temperature and 0.85 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo. Purification was done by flash chromatography to afford 1.13 g of product.