Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[C:20]([O:27]C)[CH:21]=[CH:22][CH:23]=4)[O:18]3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[BrH:29]>>[BrH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[C:20]([OH:27])[CH:21]=[CH:22][CH:23]=4)[O:18]3)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc2c1OC(CNCc1cncc(-c3ccc(F)cc3)c1)CC2
Agent: Br
Product: Oc1cccc2c1OC(CNCc1cncc(-c3ccc(F)cc3)c1)CC2

Procedure:
Analoguosly to example 2.1, (2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-8-methoxychroman is treated with hydrobromic acid to obtain (2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:36])([F:38])[F:37])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCCN(C)C)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCCN(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.4 g, 1.86 mmol) in CH2Cl2 (9 mL) was added TFA (4.5 mL), and the reaction was stirred at RT for 2 h. Then the reaction was concentrated in vacuo and the residue was partitioned between CH2Cl2 and aqueous NaHCO3, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH2Cl2/EtOH/NH4OH) provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=NC=C[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:18]1[N:19]=NC=C[CH:23]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]=[N:19][CH:18]=[CH:23][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Brc1cccnn1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2cccnn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting with 3-bromopyridazine. ESI-MS (m/z): 215 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:42])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH:25]=[CH:24][N:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:43].O1CCOCC1>CC#N>[ClH:43].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:42])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[C:22]3[CH:27]=[C:26]([O:28][CH:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)[CH:25]=[CH:24][N:23]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Yield: 77 %

Procedure:
tert-Butyl 4-(2-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-4-yloxy)piperidine-1-carboxylate from Step 3 (280 mg, 0.48 mmol) was stirred in 4N HCl/1,4-Dioxane (10 mL) for 2 h at rt. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with CH3CN (20 mL) and evaporated under reduced pressure. The residue was taken up in CH3CN/Et2O (1:5, v/v), sonicated at rt for 15 min, and filtered to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride as a yellow solid (190 mg, 77% yield). LC-MS (ESI) m/z 479 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.69 (s, 1H), 9.36 (br. s., 1H), 9.07 (br. s., 1H), 8.60 (d, J=5.84 Hz, 1H), 7.97 (br. s., 1H), 7.83 (d, J=8.85 Hz, 2H), 7.46 (d, J=9.04 Hz, 2H), 7.39 (dd, J=2.17, 5.75 Hz, 1H), 6.51 (s, 1H), 5.07 (br. s., 1H), 4.50 (br. s., 1H), 3.25 (br. s., 2H), 3.13 (d, J=3.58 Hz, 2H), 2.20 (d, J=14.32 Hz, 2H), 1.93 (d, J=9.04 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Li+].[CH2:15]([Sn](CC)(CC)CC)[CH3:16]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([CH2:15][CH3:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC[Sn](CC)(CC)CC
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cl)cc1C(=O)OC
Temperature: 100 °C
Yield: 54.7 %

Procedure:
Methyl 2-bromo-5-chlorobenzoate (1.0 g, 4 mmol), lithium chloride (490 mg, 11.58 mmol), tetraethyltin (0.81 mL, 4.1 mmol) and bis(triphenylphosphine)-palladium(II)chloride (100 mg, 0.13 mmol) were combined in DMF (20 mL) and heated at 100° C. for 5 h. Solvent was removed at reduced pressure and the residue was diluted with water and EtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 10% EtOAc/hexane) provided the title compound (435 mg, 55%).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CN(C)C1C=CN=CC=1.ClCCl>[N:5]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][CH:2]=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 46 %

Procedure:
To a cold (0° C.) solution of 1-tert-butyl 3-methyl 4-hydroxy-1,3-piperidine-dicarboxylate (1,64 g, 6.32 mmol), 4-dimethylaminopyridine (16.0 mg, 0.13 mmol), and triethylamine (2.64 mL, 19.0 mmol) in dichloromethane (25 mL) was added dropwise trifluoroacetic anhydride (1.12 mL, 7.91 mmol). The reaction mixture was stirred at room temperature for 40 hrs. The reaction was quenched with 10% K2CO3 solurtion, extracted with CHCl3. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 1-tert-butyl 3-methyl 5,6-dihydro-1,3(2H)-pyridinedicarboxylate as a pale yellow oil. (707.4 mg, yield 46%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH2:22][Cl:23])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-benzoic acid methyl ester (10 g, 54.8 mmol) and potassium carbonate (22.75 g, 164.4 mmol) in DMF (100 mL) was added 1-bromo-2-chloro-ethane (22.7 mL, 274 mmol). The mixture was heated at 70° C. for 3 h and monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine. The organic layer was dried (Na2SO4) and concentrated to afford 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (13.1 gm, 97%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 6.90 (d, 1H), 4.35 (t, 2H), 3.90 (m, 8H).
Reaction SMILES: NC(C)(CC1C=CC=CC=1)C#N.[C:13]([C:15]([NH:24][C:25](=[O:57])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH2:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[C:42]([CH3:47])[N:41](COC(=O)C(C)(C)C)[C:40]3=[O:56])[CH2:33][C:34]#[CH:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[N:14].N>CO>[C:13]([C:15]([NH:24][C:25](=[O:57])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH2:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[C:42]([CH3:47])[NH:41][C:40]3=[O:56])[CH2:33][C:34]#[CH:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[N:14]
Reactant: C#CCN(Cc1ccc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)NC(C)(C#N)Cc2ccccc2)cc1
Agent: CC(N)(C#N)Cc1ccccc1
Agent: N
Solvent: CO
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NC(C)(C#N)Cc2ccccc2)cc1
Reaction time: 24 h

Procedure:
The process described in Example 1 was repeated except that (R/S)-2-amino-2-methyl-3-phenylpropiononitrile (Eur. J. Med. Chem. Clin. Ther., 1975, 10, 117) was used in place of (-)-(2R)-2-amino-2-phenylethanol and that the N-(2-cyano-1-phenylprop-2-yl)-p-[N-(2-methyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide so produced was dissolved in methanol which had been saturated with ammonia gas and the mixture was stirred at laboratory temperature for 24 hours. The mixture was evaporated to give N-(2-cyano-1-phenylprop-2-yl)-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide, m.p. 208°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]([NH:17]C(=O)C(Cl)(Cl)Cl)=[O:16])=[C:11]([C:24]([O:26]C)=O)[CH:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[C:32]([O:36][C:37]([N:39]1[CH2:45][CH2:44][CH2:43][CH2:42][C@H:41]([NH2:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O.O>[NH2:17][C:15]([NH:14][C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[C:24]([NH:46][C@H:41]1[CH2:42][CH2:43][CH2:44][CH2:45][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]1)=[O:26])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H](N)C1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCCN(C(=O)OC(C)(C)C)C3)c(NC(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of methyl 5-(4-methoxyphenyl)-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (1.36 g, 3 mmol) in anhydrous THF (20 mL) was added a solution of [Me2Al-3-Boc-(S)-3-aminohomopiperidine] in THF (preformed by the careful addition of Me3Al (2.0 M in hexanes, 3.0 mL, 6.0 mmol) to a solution of (S)-3-amino-azepane-1-carboxylic acid tert-butyl ester in 10 nL of THF at −78° C. followed by warming to room temperature under nitrogen and stirring for an additional 15 min.). The resulting deep yellow/orange solution was stirred overnight at room temperature. The reaction mixture was cooled with ice and a 10% aqueous solution of Rochelle's salt was added slowly to quench the reaction. The resulting biphasic solution was warmed to room temperature and stirred for an additional 1 h. The mixture was diluted with EtOAc and H2O, the aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with H2O, brine and dried (Na2SO4). Evaporation gave a pale orange solid. Purification by ISCO MPLC (SiO2, 60-80% EtOAc/hexanes) gave 0.9 g (62%) of the title compound as a white solid. 1H NMR (d6-DMSO, δ 11.0, s, 1H, δ 7.95, d, 0.5H, δ 7.81, d, 0.5H, δ 7.65, s, 0.5H; δ 7.56, s, 0.5H; δ 7.46, d, 2H; δ 6.97, d, 2H; δ 6.96, br s, 2H; δ 4.19, m, 0.5H; δ 4.11, m, 0.5H; δ 3.77, m, 3H; δ 3.65, m, 1H; δ 3.48, m, 1H; δ 3.20, m, 2H; δ 1.75, m, 3H; δ 1.58, m, 2H; δ 1.42, s, 4.5H; δ 1.39, m, 1H; δ 1.36, s, 4.5H), LC/MS (APCI, ES, M+H=489).
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH3:34])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCC(=O)O)CCC3)cc1
Temperature: 50 °C

Procedure:
A solution of ethyl 6-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)hexanoate (step 1)(2.8 g, 6.12 mmol) in MeOH (50 ml) was treated with 1M sodium hydroxide (9.18 ml, 18.36 mmol) and the resulting white suspension was heated at 50° C. for 2 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water, acidified (pH 4, 2N HCl) and extracted with DCM (×3). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford an oil which crystallized to yield the titled compound as an off-white solid;
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)O1.[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31](Br)=[N:32][CH:33]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:13][CH:14]=2)=[N:32][CH:33]=1)=[O:28]
Reactant: CC1(C)OB(c2ccc(-n3cnc4ccccc43)cc2)OC1(C)C
Reactant: COC(=O)c1cnc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2ccc(-n3cnc4ccccc43)cc2)n1C
Temperature: 90 °C
Yield: 36 %

Procedure:
To a solution of 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazole (0.43 g, 1.5 mmol) and 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (0.25 g, 1.15 mmol) in DME (9 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.057 mmol) and 2 M aqueous potassium carbonate (1.4 mL) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was filtered and the filtrate washed with water, dried (Na2SO4), and the solvent removed under reduced pressure. Purification by flash column chromatography (silica, petroleum ether:ethyl acetate 7:3→1:1 then dichloromethane:methanol 99:1→97:3) provided the title compound (36%). LCMS (ESI+) 332.2 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[ClH:17].[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCOCC2)c(OCCN2CCOCC2)c1

Procedure:
2-Morpholin-4-yl-5-nitrophenol and 4-(2-chloroethyl)morpholine were allowed to undergo the reaction in DMF in the presence of potassium carbonate, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 and further treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 4-morpholin-4-yl-3-(2-morpholin-4-ylethoxy) aniline hydrochloride. F: 308.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](O)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CO
Reactant: NCCc1ccccc1
Product: O=CNCCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A mixture of phenylethylamine (20.0 g, 0.165 mol) and formic acid (49.4 ml, 1.309 mol) was slowly heated to 200° C. Excess water and formic acid were distilled off in the process. The mixture was then kept at 200° C. for 1 hour, and the product was distilled under reduced pressure, giving a colourless oil (22.0 g, 0.147 mol, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[F:21][C:18]1([F:22])[CH2:17][CH2:16][CH:15]([CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11])[CH2:20][CH2:19]1
Reactant: COC(=O)[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(F)(F)CC1
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propanoate (28.6 g, 0.089 mol), prepared as described in U.S. Pat. No. 5,688,946, in ethanol (600 mL) at 0° C. was added NaBH4 (27.1 g, 0.713 mol) in portions while the temp. was maintained at 0-5° C. The mixture was stirred for 2-3 h at rt and then evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (S)-tert-butyl 1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (25.7 g, 99%), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): 4.61 (d, J=7.6 Hz, 1H), 3.70 (m, 1H), 3.50 (m, 1H), 2.45-1.10 (m, 11H), 1.44 (s, 9H); MS (E/Z): 295 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([CH3:6])([CH3:5])[CH3:4].F[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]1[CH:30]=[N:29][C:28]([CH3:31])=[N:27]1>C1COCC1>[CH3:31][C:28]1[N:29]=[CH:30][N:26]([C:18]2[CH:17]=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][C:19]=2[O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:15])[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[N:27]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
Sodium hydride (0.405 g, 10.13 mmol) was suspended in THF (6 mL), and then tert-butyl-(4-hydroxybutyl)carbamate (1.278 g, 6.75 mmol) in THF (6.0 mL) was added. The reaction mixture was stirred at 0° C. for 10 min, followed by the addition of 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.0 g, 4.50 mmol) in THF (10.0 mL). The mixture was stirred at 0° C. for 1 h and then stirred for an additional 2 h at rt. The reaction was quenched with water and extracted with EtOAc three times. After concentrating the combined EtOAc layers, the residue was purified by flash chromatography (silica gel, 300 g, 0 to 80% EtOAc/Hexane) to get tert-butyl (4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)carbamate (1.75 g, 99% yield). LC-MS (M+Na)+=414.5. 1H NMR (500 MHz, chloroform-d) δ 8.88 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.9, 2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H), 4.28 (t, J=6.5 Hz, 2H), 3.22 (d, J=6.4 Hz, 2H), 2.52 (s, 3H), 2.01-1.92 (m, 2H), 1.74-1.68 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([O:33]C)=[O:32])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([OH:33])=[O:32])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccccc2)cc1
Temperature: 50 °C
Yield: 103.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23 g) as yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([C:15]3[N:16]=[CH:17][N:18]([C:20](C4C=CC=CC=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:39]([O:41]C)=O.CO.[CH3:45][NH2:46]>C1COCC1>[CH3:45][N:46]1[CH2:2][C:3]2[C:12]3[CH:11]=[CH:10][C:9]([C:13]([C:15]4[N:16]=[CH:17][N:18]([C:20]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:3]5[CH:12]=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH:19]=4)=[O:14])=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:39]1=[O:41]
Reactant: COC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1CBr
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CN1Cc2c(ccc3cc(C(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 1-bromomethyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthoate (14.0 g) was dissolved in THF (120 mL), and 40% methylamine methanol solution (60 mL) was added. The reaction mixture was stirred at room temperature for 20 hrs. and the solvent was evaporated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=40:1) and crystallized from ethyl acetate-diethyl ether to give the title compound (5.5 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1ccc(F)cc1
Product: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Yield: 84 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-fluorophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde (84% yield) as a cream solid. ESI/MS 274 (M+H); RT=3.64 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=6 Hz); 7.72 (2H, m); 7.58 (2H, m); 7.39 (2H, m); 7.12(1H, d, J=9 Hz).