Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)(O)[O-].[Na+].[I-:16].[K+].II>O.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[C:8]([I:16])[C:6]=2[N:7]=1
Reactant: [I-]
Reactant: Clc1ncc2[nH]ccc2n1
Agent: II
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Product: Clc1ncc2[nH]cc(I)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a suspension of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (3.55 g, 23.2 mmol) in water (200 ml) was added sodium bicarbonate (19.2 g) A solution of potassium iodide (16.41 g, 98.9 mmol) and iodine (5.78 g, 22.8 mmol) in water (25 ml) was added dropwise then allowed to stir at room temperature for 1 h. The mixture was diluted with brine and extracted with ethyl acetate. The extracts were dried filtered and evaporated. The residue was purified by flash chromatography, eluting with chloroform/methanol 25/1 to 20/1, to afford 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (5.33 g, 83%). 1H NMR (DMSO, 300 MHz): 12.50 (s, 1H), 8.82 (s, 1H), 8.20 (s, 1H); 13C NMR (DMSO, 75 MHz): 143.2, 143.0, 139.7, 139.5, 126.5, 56.2; LRMS (EI): m/z calcd for [M]+ 278.91, 280.91 found 278.95, 280.95.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14]/[C:15]/2=C\C(O)=O)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14]/[C:15]/2=[CH:1]\[C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCCc2ccc(F)cc21
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (3 ml, 0.034 mol, Aldrich) was added to a suspension of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid (2.03 g, 0.01 mol) in toluene (35 ml) at 0° C. while protected from moisture by a nitrogen atmosphere. The stirring mixture was allowed to warm to 25° C. and was stirred for 1.5 h. Concentration in vacuo gave (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride which was dissolved in dichloromethane and used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1C(=O)OC

Procedure:
A mixture of methyl 5-chloro-2-hydroxybenzoate (2c) (45.0 g, 0.24 mol), allyl bromide (62.6 ml, 0.75 mol) and ground potassium carbonate (66.67 g, 0.48 mol) in 750 ml of dry acetone was heated under reflux for 21/2 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide in the filtrate was evaporated to dryness to yield compound 3c quantitatively as a white solid, mp 25°-26° C. IR (nujol) 1738 (ester) cm-1. NMR (CDCl3) δ7.63 (d, 1H, JBC =3 Hz, HC), 7.27 (d of d, 1H, JAB =9 Hz, HB), 6.77 (d. 1H, HA), 6.30-6.47 (m, 3H, olefinic protons) and 3.87 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>O1CCOCC1>[Cl:22][C:21]1[C:16]([OH:15])=[C:17]([S:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:26])=[O:25])[CH:18]=[C:19]([Cl:23])[CH:20]=1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: O
Solvent: C1COCCO1
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g (0.02 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 40 ml of dioxane (containing 1.6 ml pyridine) is added a solution of 5.3 g (0.02 mol) of 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride in 15 ml dioxane. The second solution is slowly added to the first over a 10-minute period. The reaction mixture (which takes on an orange color) is stirred for 2 hours at room temperature and then left for 16 hours. Water is added and the precipitate is filtered off and dried, giving the pink, fluffy 3-[4-(3,5-dichloro-2-hydroxy benzenesulfonamido)-benzenesulfonyl]acrylonitrile: ##SPC28##
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(Br)ccc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(-c3cccnc3)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1 (a). 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example 32(b), (67 mg, 0.18 mmol) reacted with 3-pyridine boronic acid (24 mg, 0.2 mmol, Fluorochem) to give the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 376 (M+1).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@H:11]2[NH:12][CH2:13][C@@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@@H]2C[C@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.8 %

Procedure:
tert-Butyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (1.13 g) was dissolved in trifluoroacetic acid (50 ml) and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a pink solid. Trituration with cold acetonitrile gave (3S,5S)-5[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol as a brown solid (380 mg, 51%); NMR spectrum (DMSO-d6) 10.38-10.54 (br s, 1H), 8.52 (s, 1H), 8.36 (dd, 1H), 7.94-7.99 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.79 (d, 1H), 4.75 (d, 1H), 4.41 (dd, 1H), 4.26-4.34 (m, 1H), 4.17 (t, 1H), 3.94 (s, 3H), 3.54-3.73 (m, 1H), 2.96 (dd, 1H), 2.79 (dd, 1H), 2.11-2.20 (m, 1H), 1.41-1.49 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: C([O:8][NH:9][C:10]([C@@H:12]1[C@@H:17]([C:18](=[O:39])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH:14]([CH2:40][C:41](O)=[O:42])[CH2:13]1)=[O:11])C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1.CN1CCOCC1>CN(C=O)C>[OH:8][NH:9][C:10]([C@H:12]1[CH2:13][CH:14]([CH2:40][C:41](=[O:42])[N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)[CH2:15][CH2:16][C@@H:17]1[C:18]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[CH:22][CH:21]=1)=[O:39])=[O:11]
Reactant: C1CCNCC1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
Part 10: 4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(S)-,2-(S)-dicarboxylic acid 2-(S)-(benzyloxy-amide) 1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: {3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid (20 mg, 0.034 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg, 0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine (0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 10% methanol in methylene chloride over 30 min) to afford 21 mg (95%) of the desired amide. LCMS (ESI): 649 (M+1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1COCC1>CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccnc2)c1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1

Procedure:
Hydrogenation of a stirred solution of 3-nitro-N-pyridin-3-ylmethyl-benzenesulfonamide [CAS-No. 436095-43-1; commercially available] (1.42 g, 4.84 mmol) in methanol (90 ml) and THF (50 ml) on palladium/carbon (10%, 0.14 g) for 2 h at room temperature yielded after removal of the catalyst by filtration, evaporation and crystallization from ethyl acetate/hexane the title compound (1.15 g, 90%) as a light yellow solid. MS (ISP) 264.1 [(M+H)+]; mp 129° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[CH:13]=[N:14][N:15]([CH:20]([CH3:22])[CH3:21])[C:16]=2[C:17](O)=[O:18])[CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:12]3[CH:13]=[N:14][N:15]([CH:20]([CH3:21])[CH3:22])[C:16]=3[C:17]2=[O:18])[CH:3]=1
Reactant: CC(C)n1ncc(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c1C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)n1ncc2c1C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxylic acid (Step 38.2). tR: 4.55 min (HPLC 1); tR: 1.02 min (LC-MS 2); ESI-MS: 417 [M+H]+ (LC-MS 2); Rf=0.41 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.55 (m, 6H) 3.43 (s, 3H) 4.75-4.86 (m, 1H) 6.13 (s, 1H) 7.21-7.28 (m, 2H) 7.34-7.40 (m, 2H) 7.42 (s, 1H) 7.89 (d, J=2.7 Hz, 1H) 7.94 (d, J=2.7 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>O1CCCC1>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([O:11][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC(CC(O)C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(CC(O)C(=O)OCc2ccccc2)N1

Procedure:
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.1 g), triethylamine (1.2 g), N-N-dimethylaminopyridine (1.5 g), and benzyl chloroformate (17 g) in 40 ml tetrahydrofuran is heated at reflux for 16 hours. After cooling and filtering off the triethylamine-hydrochloride, the solution was concentrated and chromatographed on SiO2 (elution with methanol:chloroform; 3:97) to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, benzyl ester mp 95°-96° C. NMR (CDCl3) and 7.37 (s, 5H), 7.93 (d, 1H), 5.40 (s, 1H), 1.70 (m, 2H). IR (KBr) 3330, 3200, 1733, 1691, 1497, 1456, 1389, 1351, 1287, 1216.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=O)(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@@H](C(=O)O)C1
Yield: 86 %

Procedure:
A mixture of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid in a 1:1 solution of TFA: CH2Cl2 (6 mL) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure. The residue was triturated in ethyl ether (50 mL) and the resulting solid was collected by filtration to afford (1R,3R)-3-aminocyclohexanecarboxylic acid trifluoroacetate (253 mg, 86%) as a white solid that did not require further purification.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO[C:23](/[N:25]=N/C(OCC)=O)=O.[NH2:32][CH:33]1[C:42]2[C:37](=[CH:38][C:39]([CH2:43]O)=[CH:40][CH:41]=2)[O:36][CH2:35][CH2:34]1.CC(C)(O)C#N>C1COCC1>[NH2:32][CH:33]1[C:42]2[C:37](=[CH:38][C:39]([CH2:43][C:23]#[N:25])=[CH:40][CH:41]=2)[O:36][CH2:35][CH2:34]1
Reactant: NC1CCOc2cc(CO)ccc21
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1ccc2c(c1)OCCC2N
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a 125 mL flame dry 3-neck round bottom flask was added P(Ph)3 (4.4 g, 16.74 mmol) and THF (50 mL). After cooling to −20° C., DEAD (3.3 mL, 16.74 mmol) was added dropwise via the addition funnel. After stirring for 20 min at −20° C., (4-aminochroman-7-yl)-methanol (2.0 g, 11.16 mmol) in THF (75 mL) was added dropwise via the addition funnel. It was stirred for another 30 min. acetone cyanohydrin (3.1 mL, 33.48 mmol) was then added dropwise via the addition funnel. The resulting mixture was warmed to RT and stirred for 18 h. Solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound. MS m/z: 189.12 (M+H). Calc'd. for C11H12N2O-188.23.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[N+]([NH:31][C:32](N)=[O:33])([O-])=O.O>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][N:25]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:23]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1ccc2c(c1)c(C1CCNCC1)nn2-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole free base of Example 124 (6.3 g, 0.017 moles) in DMF (100 ml) was added nitrourea (2.2 g, 0.021 moles). The mixture was warmed on a steam bath until gas began to evolve and was then stirred at ambient temperature for 4 hours. The mixture was then poured into H2O and the product extracted (dichloromethane), dried (MgSO4), and concentrated to yield 6.9 of an oil. The oil was triturated with water to produce 6.9 of a solid. The product was purified by high pressure liquid chromatography (silica gel 100% ethyl acetate) followed by recrystallization from isopropyl alcohol to yield 2.75 g (39%) of 4-[5-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, mp 172°-174°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH2:10]OC)OC.Br[C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C(Cl)(Cl)Cl>[C:23]1([C:14]2[CH:15]=[N:16][C:19]3[C:7]([CH:10]=2)=[CH:21][CH:22]=[CH:17][CH:18]=3)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:23]=1
Reactant: COCCOC
Reactant: Brc1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: c1ccc2ncc(-c3cccc4ccccc34)cc2c1
Temperature: 90 °C

Procedure:
Next, 1.0 mL of 2.0 M potassium carbonate aqueous solution and tris(triphenylphosphine)palladium [Pd(PPh3)4] (30 mg, 0.026 mmol) were added to 4 mL of dimethoxyethane (DME) solution of the 1-naphthylboronic acid ester (2-1) (1.00 g, 5.00 mmol) and 3-bromoquinoline (0.62 g, 3.00 mmol), which then was refluxed at 90° C. for 12 hours. After completion of the reaction, it was cooled to room temperature, and 100 mL of chloroform was added thereto. This was washed with 100 mL of water twice and subsequently was washed with 50 mL of saturated saline. The solvent was removed therefrom and this then was purified by column chromatography using chloroform as a developing solvent. Thus 3-(1-naphthyl)quinoline (2-2) was obtained (84 mg, 11%). The instrumental analysis data of this 3-(1-naphthyl)quinoline (2-2) is indicated below.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C:17]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:17]([NH:34][C@H:35]([C:39]([O:16][CH2:15][CH:2]([OH:1])[CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[O:40])[CH:36]([CH3:37])[CH3:38])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(C=CC(O)CO)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 4,5-dihydroxy-2-pentenoate (4.4 g, 20 mmole), N-FMOC-L-valine (5.8 g, 17 mmole) and DMAP (0.21 g, 1.7 mmole) in 100 ml dichloromethane was cooled to about 10° C. A solution of DCC (4.2 g, 20 mmole) in 25 ml dichloromethane was added dropwise at the same temperature and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evaporated under reduced pressure and the product was isolated by silica gel column chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8]2)[N:6](C(OC(C)(C)C)=O)[CH2:5][C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]1[CH2:27][C:28](=[O:48])[NH:29][C:30]1[CH:31]=[C:32]2[C:45](=[CH:46][CH:47]=1)[CH2:44][C@:34]1([C:42]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]1=[O:43])[CH2:33]2.Cl>CO>[O:43]=[C:35]1[NH:36][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:42]2[C@:34]21[CH2:33][C:32]1[C:45](=[CH:46][CH:47]=[C:30]([NH:29][C:28](=[O:48])[CH2:27][N:3]3[C:2](=[O:1])[C:7]4([CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8]4)[NH:6][CH2:5][C@H:4]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:31]=1)[CH2:44]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Agent: Cl
Solvent: CO
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1ccccc1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
0.27 g (0.41 mmol) (R)-tert-butyl 5-oxo-4-(2-oxo-2-((R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[inden-2,3′-pyrrolo-[2,3-b]pyridin]-5-ylamino)ethyl)-3-phenyl-8,11-dioxa-1,4-diazaspiro[5.6]-dodecane-1-carboxylate in 5 ml of methanol were combined with 10 ml of a 1.25 M methanolic hydrochloric acid and stirred for 3 h at 50° C. The reaction mixture was concentrated by rotary evaporation and neutralised with saturated NaHCO3 solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:20][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:7]([O-:9])=[O:8]
Reactant: Cn1cc([N+](=O)[O-])cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to −78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to −45 C over 30 min. The mixture was cooled back down to −78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from −78 C to −40 C and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2Cl2/7% MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-])=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[NH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:19][C:13]1([CH:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
2-(dibenzylamino)-2-(1-hydroxycyclohexyl)acetic acid (0.70 g, 1.98 mmol, Eq: 1.00) and 1-fluoro-2-nitrobenzene (293 mg, 219 μl, 2.08 mmol, Eq: 1.05) were dissolved in THF (10 mL) and a solution of potassium bis(trimethylsilyl)amide 0.5 M in toluene (8.71 mL, 4.36 mmol, Eq: 2.2) was added. The mixture was heated to 60° C. After 1 h the mixture was cooled to RT and 0.2 mL 1-fluoro-2-nitrobenzene and an additional 9 mL of potassium bis(trimethylsilyl)amide (0.5 M in toluene) were added and the mixture stirred at 60° C. for 90 min. The mixture was diluted with H2O, acidified with sat. KHSO4, and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 2-(1-(2-aminophenoxyl)cyclohexyl)-2-(dibenzylamino)acetic acid as a light brown oil (0.80 g, 85%). MS m/z 475.1 (MH+)