Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:34])[N:8]2[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]1)(=[O:3])[NH2:2].C(OC(N[C@H]1CC[C@H](N2C(=O)NC3C2=NC(C2C=CC=C(O)C=2)=NC=3C(OCC)=O)CC1)=O)(C)(C)C.N>CO>[NH2:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:8]2[C:7](=[O:34])[NH:6][C:5]3[C:9]2=[N:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[N:12][C:4]=3[C:1]([NH2:2])=[O:3])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2c(=O)[nH]c3c(C(N)=O)nc(-c4cccc(O)c4)nc32)CC1
Agent: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@H](N)CC1
Reaction time: 16 h

Procedure:
tert-Butyl trans-4-(6-carbamoyl-2-(3-hydroxyphenyl)-8-oxo-7H-purin-9(8H)-yl)cyclohexylcarbamate. Ethyl 9-(trans-4-(tert-butoxycarbonylamino)cyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.070 g, 0.140 mmol) and ammonia in methanol were reacted according to General Procedure G. After 16 h, LCMS confirms product and the solution was condensed under reduced pressure to afford the title compound (0.040 g, 60%). MS (ESI) m/z 469 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]([C@@H:20]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:36])=[N:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[ClH:37].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:37].[CH:1]1([N:4]([C@@H:20]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:36])=[N:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCn1nc(C)c2ccc([C@@H](C)N(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COCCCn1nc(C)c2ccc([C@@H](C)N(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate (44.4 mg) in chloroform (2.0 mL) was added 4-normal hydrogen chloride-dioxane solution (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water (1 mL), and then washed with diethyl ether. The aqueous layer was freeze-dried to give (2R)-N-cyclopropyl-N-{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}morpholine-2-carboxamide hydrochloride [Ex(3-1)] (25 mg) as a colorless powder.
Reaction SMILES: [CH3:1]Cl.[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22].[Br-].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][C:9]([CH3:1])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: CCl
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 35 ml glass pressure bottle, fitted with an efficient magnetic stirrer was charged with 25 ml of toluene. Methyl chloride (1.01 g, 20 mmole) were dissolved in the toluene and to this solution there were added 0.61 g (2 mmole) of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone, 0.21 g (0.4 mole) of N-p-(trifluoromethylbenzyl) cinchoninium bromide and 5 ml of 50% aqueous sodium hydroxide. The reaction mixture was sealed with a screw cap and vigorously stirred for 18 hours at room temperature (22°-25° C.). The reaction mixture was then diluted with 25 ml of toluene and 15 ml of water. The aqueous layer was separated and the toluene layer was washed twice with 25 ml of 4N hydrochloric acid. An aliquot of the toluene solution was concentrated in vacuo to dryness on a rotary evaporator. An LC assay indicated a 98% yield while an NMR assay using the chiral shift reagent [tris-[3-heptafluoropropylhydroxymethylene)-d-camphorato]europium (III)] showed a (+):(-) isomer ratio of 95.3:4.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Li])CCC.[B:17]([O:26][CH:27]([CH3:29])C)([O:22][CH:23](C)C)OC(C)C.C(Cl)(=O)C.C(O)CCO>C(OCC)C.C1COCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]2[O:22][CH2:23][CH2:29][CH2:27][O:26]2)=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1c(Cl)ccc(Br)c1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)Cl
Product: COc1c(Cl)ccc(B2OCCCO2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 144.2 %

Procedure:
To a solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4 g, 0.043 mol) in diethyl ether (150 mL) at −78° C. was slowly added n-butyl lithium (2.5M, 19.0 mL, 0.0475 mol) and the solution was stirred for 30 minutes. A solution of triisopropyl borate (12.0 g, 0.064 ml) in THF (25 mL) was slowly added and the solution was warmed to a 0° C. Acetyl chloride (10.0 g, 0.13 mol) was added. After stirring for 1 hour, the solution was concentrated and the solid residue taken into ethyl acetate (150 mL) and a 1N solution of sodium hydroxide (50 mL). Ice was added to the aqueous phase which was then acidified with sufficient concentrated hydrochloric acid to obtain a pH of 2. The heterogeneous mixture was extracted with ethyl acetate (2×150 mL) and the combined organic phases dried (sodium sulfate) and concentrated. The resulting solid was slurried in toluene and propane-1,3-diol (6.6 g, 0.09 mol) was added and the mixture heated under reflux with water being removed with a Dean-Stark trap. After 2 hours the mixture was cooled and concentrated. The resulting oil was taken into methylene chloride (50 mL) and washed with water (25 mL), then dried (sodium sulfate) and concentrated to give 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (6.4 g, 0.062 mol): 1H NMR (CDCl3): δ 7.15 (m, 1H), 6.95 (dd, 1H), 4.05 (t, 4H), 3.8 (s, 3H), 1.95 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=3)=[C:22]([O:33][CH3:34])[CH:21]=2)[N:7]=1)=C)[CH3:2].I([O-])(=O)(=O)=[O:36].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[K]>O1CCOCC1.O>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:36])[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=2)[CH:25]=[CH:24][C:23]=1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[N:28][CH:27]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Temperature: 25 °C

Procedure:
4-(1-Ethoxyvinyl)-N-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-2-amine (0.7 g, 1.47 mmol) was dissolved in 1,4-dioxane (50 mL). Sodium metaperiodate (0.630 g, 2.94 mmol) was suspended in water (25 mL) and sonicated until a clear solution was obtained then added to the dioxane-solution. Potassium permanganate (0.035 g, 0.22 mmol) was added and the mixture was stirred at rt. Additional 10-15 mg of potassium permangante was added every 10 min. After 45 min the reaction mixture was filtered and the filter was washed with EtOAc. To the filtrate were sodium bicarbonate (s) and sodium chloride (s) added and the mixture was stirred for 5 min. The phases were separated and aqueous layer was extracted with ethyl acetate (×2). The combined organic layer was dried over sodium sulfate, filtrated and evaporated. The residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound as a solid, 595 mg (85%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)[CH:9]=1)=[O:7].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH:9]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC2C=C(C(=O)c3ccco3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1=CC2CNCC2C1)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromofuran (0.11 g, 0.74 mmol) in THF (3 mL) at −78° C. was added n-BuLi solution (2.5 M solution in hexanes, 0.30 mL, 0.75 mmol) and the mixture was stirred for 1 h. A solution of N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide (0.20 g, 0.65 mmol) in THF (2 mL) was added, and the mixture was warmed to ambient temperature over 8 h. The reaction was quenched with water (0.2 mL), diluted with of ethyl (20 mL) acetate, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude product was purified on silica gel column chromatography to obtain 0.10 g of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone and 0.06 g of recovered starting material. A sample of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone (0.050 g, 0.16 mmol) was dissolved in dichloromethane (3 mL), treated with TFA (2.0 mL), and stirred at ambient temperature for 1 h. The volatiles were evaporated, and the product was vacuum dried to obtain 0.047 g of 2-furanyl(3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone trifluoroacetate (1H NMR (CD3OD, 300 MHz): δ 7.81-7.80 (m, 1H), 7.38-7.36 (m, 1H), 6.91-6.88 (m, 1H), 6.65 (dd, J=3.66, 1.71 Hz), 3.95-3.86 (m, 1H), 3.56-3.40 (m, 3H), 3.27-3.16 (m, 1H), 3.14-3.02 (m, 2H), 2.77-2.68 (m, 1H); MS (m/z): 204 (M+1)). This material exhibited Ki values at rat and human α4β2 of 8 nM and 2 nM respectively and did not pass HTS for α7.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([N+:10]([O-])=O)[C:4]=1[CH3:13]>C1COCC1.[H][H].[Ni]>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:14])[CH3:1])=[C:4]([CH3:13])[C:5]=1[NH2:10]
Reactant: [H][H]
Reactant: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1c(N(C)C)ccc(Br)c1N
Yield: 90.5 %

Procedure:
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is dissolved in about 200 ml of THF and hydrogenated at 20° C. under 5 bars pressure of hydrogen using Raney nickel as catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline is obtained as a brown oil.
Reaction SMILES: [C:1]([C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][NH2:40].N1C=CC=CC=1>CO.O>[CH3:38][O:39][N:40]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:34][CH:35]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: CON
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1

Procedure:
The compound obtained in Example 18 is dissolved in a minimum of methanol and then 4 equivalents of O-methylhydroxylamine, previously dissolved in a few milliliters of water, and 4.5 equivalents of pyridine are added in succession. The reaction mixture is heated at reflux for 24 hours and then hydrolysed in water and filtered; the resulting precipitate is recrystallised from methanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[O:24])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[CH:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)[OH:24])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Yield: 91.6 %

Procedure:
Dissolve the compound of Example 74 (200 mg, 0.37 mmol) in THF (30 mL). Add lithium aluminum hydride (LAH, 70.3 mg). Quench with ice and water. Acidify with 1M aqueous HCl and make the solution slightly basic with aqueous NaHCO3. Extract with 25% i-PrOH in CHCl3. Purify the crude product using an SCX column eluting with 2M NH3/MeOH to afford 185 mg of the title compound (92%) LCMS: m/z=546 (M+H)+
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:21])[CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Cl:10][C:11]1[C:19]([F:20])=[CH:18][C:14]([C:15]([N:65]2[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)=[O:49])[CH2:67][CH2:66]2)=[O:17])=[C:13]([F:21])[CH:12]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-chloro-2,5-difluoro-benzoic acid (49.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 65 mg (50.7% yield) of biphenyl-4-carboxylicacid {2-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.40%, 1H NMR: (DMSO) δ 8.7-8.6 (s, 1H), 8.04-7.92 (d, 2H), 7.88-7.7 (q, 5H), 7.7-7.6 (s, 1H), 7.58-7.46 (d, 2H), 7.46-7.38 (d, 1H), 4.3-4.12 (d, 2H), 3.8-3.58 (d, 5H), 3.56-3.44 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH:31]([F:33])[F:32])[C:25]3=[N:24][CH:23]=2)=[N:5][C:6]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=[O:16])[CH3:11])=[N:7][CH:8]=1)#[N:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:3]1[C:4]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH:31]([F:32])[F:33])[C:25]3=[N:24][CH:23]=2)=[N:5][C:6]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[CH3:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc(C(C)Nc2ncc(C#N)c(-c3cnc4c(C(F)F)cccn34)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
370 mg of the methyl 3-[1-({5-cyano-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amino)ethyl]benzoate [100-3] was suspended in a mixture solvent of 6 mL of methanol and 6 mL of tetrahydrofuran, then 4.15 mL of 1N aqueous solution of sodium hydroxide was added, and stirred at 50° C. for 30 minutes. Under an ice-cold condition, 825 μL of 5N hydrochloric acid was added, then the reaction solution was neutralized and concentrated under reduced pressure. The obtained residue was purified by preparative reversed phase liquid chromatography, and 216 mg of 3-[1-({5-cyano-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amino)ethyl] benzoic acid [100-4] was obtained as a pale yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]([CH2:17][C:18](=[O:20])[CH3:19])[N:15]=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:4].[BH4-].[Li+].C([O-])([O-])=O.[Na+].[Na+].Cl.CCO>CO.C(Cl)(Cl)Cl.CCOCC>[ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[N:15]=[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n(CC(C)=O)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n(CC(C)O)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a stirred solution of 1-[5-(3-dimethylaminomethyl-phenyl)-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-propan-2-one hydrochloride (22 mg, 0.05 mmol) in methanol (4 ml), was added Lithium borohydride (1.8 mg, 0.08 mmol) and the mixture stirred for 4 hr at r.t. Saturated Na2CO3 solution was then added and the mixture stirred for 15 min., the aqueous phase was then extracted twice with EtOAc, dried with Na2SO4 filtered and the solvent evaporated to afford a yellow oil. This was dissolved in CHCl3 and 1.45N HCl/EtOH (0.05 ml) was added at 4° C. After 20 min ether was added to precipitate the titled salt as a light brown solid (17 mg, 76.9% yield) MS: m/e=367.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=3[O-])[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1>C(O)C.[C].[Pd]>[NH2:21][C:20]1[C:2]([NH2:1])=[CH:3][C:4]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]=2[CH:19]=1
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])c(N)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CN(c2ccccn2)c2cc(N)c(N)cc2O1

Procedure:
To a suspension of 948 mg 2-(7-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide in 180 ml ethanol, was added a catalytic amount of 10% palladium-carbon powder, and catalytic hydrogenation was performed at ordinary temperature and pressure. The catalyst was filtered off from the reaction mixture, and the solvent was distilled off from the filtrate, thus giving crude 6,7-diamino-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1,4-benzoxazine. This product was immediately used for the succeeding reaction.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:5]([C:15]([O:17]CC)=O)[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].[OH-].[Na+].O.Cl.C[N:33](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(#N)C.C(Cl)Cl>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:5]([C:15]([NH2:33])=[O:17])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1c(-c2ccnc(F)c2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxylate (2.33 g, 0.00553 mol) was dissolved in acetonitrile (100 mL) and 1M sodium hydroxide in water (42 mL, 0.0420 mol) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was acidified with 1N HCl. The solid was collected, dried, and used in the next step without purification. The above solid was dissolved in methylene chloride (248 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.29 g, 0.0120 mol) and 1-hydroxybenzotriazole hydrate (1.694 g, 0.01106 mol) were added. The mixture was stirred at room temperature for 15 minutes and 33% ammonium hydroxide (20.0 mL, 0.231 mol) was added. The stirring was continued for 2 hours. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried and purified by column chromatography on silica gel (80 g), elution hexane to 60% EtOAc in hexane over 30 minutes. The product was obtained as white solid (1.18 g, 55%). LCMS: (FA) ES+, 392, 394. 1H NMR (400 MHz, d6-DMSO) 8.50 (d, J=5.27 Hz, 1H), 7.85 (d, J=1.79 Hz, 1H), 7.79 (td, J=5.21, 1.52, 1.52 Hz, 1H), 7.65 (s, 1H), 7.63-7.55 (m, 2H), 7.42 (bs, 1H),
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Product: O=Cc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43c (1.20 g, 6.44 mmol) and phenylboronic acid (1.18 g, 9.65 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (10:1) as eluent. Light yellow solid. Yield: 1.10 g, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.44-7.52 ppm (m, 3H), 7.87 (d, J=8.2 Hz, 1H), 8.04-8.08 (m, 2H), 8.20 (dd, J=8.2, 2.2 Hz, 1H), 9.10 (dd, J=2.2, 0.6 Hz, 1H), 10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=120.5, 127.5, 129.0, 129.8, 130.4, 136.5, 138.0, 152.4, 162.2, 190.4; MS (ESI): m/z=184.31 [M+H]+.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CC(N(C)C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(CN1C(=O)c2ccccc2Nc2ncccc21)c1ccccc1
Temperature: 0 °C
Yield: 24.4 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (5.0 g, 1 eq.) was suspended in dimethylacetamide (DMA) (50 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (2.07 g, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 2-bromo-1-phenylethanone (7.04 g, 1.5 eq.) was added. The reaction was stirred at room temperature before the addition of a further quantity of 2-bromo-1-phenylethanone (9 g, 2 eq.). The reaction was quenched after 2 hours at room temperature (the reaction did not proceed to completion). The reaction was poured onto 200 mL water and extracted with dichloromethane (3×75 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-5% methanol in dichloromethane) gave 5-(2-oxo-2-phenylethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.9 g, 24%) as a red solid. LCMS: 330 [M+H].