Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([F:36])[CH3:35])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([F:36])[CH3:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(F)COS(=O)(=O)C(F)(F)F
Product: COc1cn(C(CC(C)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.24 ml (1.24 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 356 mg (1.69 mmol, 1.5 eq.) of 2-fluoropropyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 270 mg (52% of theory)
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]=[C:7]=[NH:8])C.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18].CS(O)(=O)=O>C(O)C>[NH:19]1[CH:17]=[CH:16][N:8]=[C:7]1[NH:6][C:5]1[CH:4]=[C:13]([NH:19][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:23])([F:24])[F:12])[CH:15]=2)[CH:14]=[CH:22][C:21]=1[CH3:20]
Reactant: CCOC(CN=C=N)OCC
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1ncc[nH]1
Reaction time: 8 h

Procedure:
A mixture of N-(2,2-diethoxyethyl)carbodiimide (398 mg, 2.51 mmol), 3-amino-4-methyl-phenyl]-3-trifluoromethyl-benzamide (649 mg, 2.20 mmol), methanesulfonic acid (143 μL, 2.20 mmol) in ethanol (25 mL) is heated at reflux for 16 hours. An additional portion of N-(2,2-diethoxyethyl)carbodiimide (525 mg, 3.32 mmol) and methanesulfonic acid (143 μL, 2.20 mmol) are added. After an additional 3 hours refluxing, the reaction mixture is concentrated. The residue is dissolved in HCl (6N, 5 mL) and ethanol (5 mL). After stirring overnight, the reaction mixture is concentrated and basified with 25% NaOH solution to a pH of 14. The mixture is stirred for 30 minutes, extracted with CH2Cl2, dried, concentrated and purified by column chromatography (silica gel, eluting with 7N NH3 in methanol:dichloromethane from 2% to 4%) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>Cl.O>[NH2:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([N:1]=[N+:16]=[N-:17])[CH:7]=1
Reactant: NCCc1ccc(O)c(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(CCN)ccc1O
Temperature: 0 °C

Procedure:
2-Amino-4-(2-amino-ethyl)-phenol (1) (1 mmol) is dissolved in aqueous HCl. The solution is cooled to 0° C. and 1 mmol of NaNO2 dissolved in H2O is added slowly with stirring. The reaction mixture is maintained at 0° C. for 1 hr, then NaN3 (2 mmol) dissolved in water is added dropwise with stirring. The resulting mixture is maintained at 0° C. for 1 hr, then the cooling bath is removed and the mixture stirred overnight at ambient temperature. The product is extracted with ethyl acetate, washed with saturated NaHCO3 and H2O. The organic phase is dried with Na2SO4, then the solvent removed under vacuum. The crude product is purified by column chromatography to yield 4-(2-amino-ethyl)-2-azido-phenol (2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:3]=1.O.[NH3:14]>>[NH2:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:3]=1
Reactant: Brc1cccc(-n2cccn2)n1
Reactant: N
Solvent: O
Product: Nc1cccc(-n2cccn2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a mixture of 2-bromo-6-(1H-pyrazol-1-yl)pyridine (3.0 mmol, 669 mg) and Cu2O (0.01 mmol, 1.0 mg) in glycol in autoclave NH3 was feed. The reaction was maintained under 10 atm of NH3 at 110° C. for 24 h. After cooling to room temperature, water was added and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=6:1 as eluent) to afford a white solid (388 mg, 81% yield). 1H NMR (400 MHz, CDCl3, ppm): 8.44 (s, 1H), 7.69 (s, 1H), 7.53 (m, 1H), 7.28 (m, 1H), 6.42-6.37 (m, 2H), 4.49 (br, 2H). 13C NMR (100 MHz, CDCl3, ppm): 151.45, 142.72, 140.73, 139.91, 127.58, 125.25, 110.89, 108.23.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:18]>O1CCCC1>[Cl:18][C:1]1[NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Reactant: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was blown in to remove excess hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%).
Reaction SMILES: [F:1][C:2]1([F:38])[CH2:3][CH2:4][N:5]([C:24]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:37])=[O:25])[C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][C:15](=[N:18][OH:19])[CH2:14][CH2:13]1)=[O:11].[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:38][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:24]([C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:37])=[O:25])[C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][C:15](=[N:18][O:19][C:39](=[O:41])[CH3:40])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 51 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine in a mixture of 800 μl of acetic anhydride and 800 μl of pyridine was stirred at room temperature for eight hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid and a saturated aqueous solution of NaCl. After drying over anhydrous magnesium sulfate, the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) to give 36 mg of (Z)-4,4-difluoro-5-{2-[4-(acetoxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOc2ccccn2)c2ccccc2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOc1ccccn1)c1ccccc1

Procedure:
A solution of {2-[3-chloro-5-(phenyl-2-(pyridin-2-yloxy)-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.065 g) and trifluoroacetic acid (0.75 ml) in dichloromethane (0.75 ml) was stirred at room temperature for 2 h then concentrated under vacuum, co-evaporating with dichloromethane to give the title compound as a yellow oil (0.086 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](N1CCN(C2C(Cl)=CN=CC=2Cl)CC1)(=[O:10])=[O:9].[Cl:25]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([Cl:25])(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1Cl)N1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: O=S(=O)(Cl)c1ccccc1Cl
Yield: 59 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(2-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 2-chlorobenzene sulfonyl chloride (59% yield).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)#[N:21].N(C(OCC)=O)=NC(O[CH2:34][CH3:35])=O>C1COCC1.CCOC(C)=O>[C:14]1([CH:34]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[CH3:35])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: N#Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C#N)cc1)c1ccccc1

Procedure:
Add triphenylphosphine (7.869 g, 30 mmol) to a solution of sec-phenylethyl alcohol (1.467 g, 12 mmol), 4-cyanophenol (1.191 g, 10 mmol) and diethyl azodicarboxylate (4.528 g, 26 mmol) in anhydrous THF (50 mL) at 0° C. Stir the reaction at ambient temperature for 12 h. Dilute with EtOAc, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (±)-4-(1-phenylethoxy)-benzonitrile with a small amount of triphenylphosphine (2.49 g total).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[C:25]1([N:31]2[C:35]([S-:36])=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>CN(C)C=O>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4][C@@H:3]([CH2:2][S:36][C:35]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=[N:33][N:34]=2)[O:8]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: [S-]c1nnnn1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nnnn2-c2ccccc2)OC(C)(C)O1
Temperature: 90 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (30 g) prepared in Example 5 was dissolved in dimethylformamide (150 ml), and sodium 1-phenyl-1H-tetrazole-5-thiolate (33.9 g) prepared in Example 7 was added thereto. The reaction liquid was warmed to 90° C. and then stirred for 24 hours. The reaction liquid was cooled to room temperature, and diisopropyl ether (600 ml) and purified water (600 ml) were added thereto. The organic layer was separated, washed with purified water (600 ml), a 10% sodium bicarbonate aqueous solution (600 ml), a saturated ammonium chloride aqueous solution (600 ml) and a saturated sodium chloride aqueous solution (600 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give the title compound (40.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[OH-].[Na+]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22])=[N:3][N:4]=[CH:5]2
Reactant: Cc1ccccc1B(O)O
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccccc1-c1nncc2cc(Cl)ccc12
Temperature: 78 °C

Procedure:
A mixture of 1,6-dichlorophthalazine (1.04 g, 5.21 mmol), tetrakis(triphenylphosphine)palldium (0.30 g, 0.26 mmol), o-tolylboronic acid (0.57 g, 4.2 mmol) in 2 N aq. sodium carbonate (5 mL), 1,4-dioxane (5 mL) and ethanol (2.5 mL) was heated in a Personal Chemistry microwave at 78° C. for 45 min. The mixture was treated with 1 N sodium hydroxide (10 mL), extracted with ethyl acetate (2×35 mL). The combined ethyl acetate layers were dried and concentrated. Purification on an ISCO column (40 g, eluted with 30-75% ethyl acetate in hexanes) provided 6-chloro-1-o-tolylphthalazine as a brown amorphous solid. MS (ESI, pos. ion.) m/z: 255 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9].[OH-].[K+]>ClCCl>[NH2:27][CH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl N-(3-{4-[3-(acetylamino)phenyl]piperidino}propyl)carbamate (340 mg) in dry dichloromethane (10 mL) and stirred at room temperature for 5 h. A 10% aqueous solution of KOH was added to the reaction mixture until pH>6 and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Removal of the solvent gave the desired product (120 mg) as an oil: 1H NMR (CDCl3) δ 7.23–7.16 (apparent t, 1H, J=7.5 Hz), 6.95–6.92 (m, 1H), 3.03–2.99 (m, 2H), 2.77–2.73 (t, 2H, J=6.6 Hz), 2.50–1.60 (m, 10H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8].[N:43]1([CH2:49][CH2:50][NH2:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31](=[O:32])[NH:51][CH2:50][CH2:49][N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[C:29]([F:37])[CH:28]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8]
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cc1F
Reactant: NCCN1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NCCN5CCCCC5)c(F)c4)ccn23)c1

Procedure:
Methyl 4-(3-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoate (step 1) (50 mg, 0.087 mmol), 2-piperidin-1-yl-ethylamine (0.260 mmol), and TBD (12.07 mg, 0.087 mmol) in THF (289 μl) were heated to 70° C. for 2 days. The mixture was diluted with water (4 ml) and extracted with DCM using a phase separator. The organic portion was concentrated in vacuo and the residue was dissolved in DMSO. Purification of the crude product was carried out by preparative LC-MS. The resulting fractions were loaded onto a pre-wetted (MeOH) Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 7M ammonia in MeOH. The resulting residue was treated with 2M HCl (in EtOH, 1 equiv) and the concentrated in vacuo to afford the title compound as a hydrochloride salt;
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:20]=[C:31]1\[C:23](=[O:22])[NH:24][C:25]2[C:30]\1=[CH:29][C:28]([NH:32][C:33](=[O:35])[CH3:34])=[CH:27][CH:26]=2
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: CC(=O)Nc1ccc2c(c1)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CCC3)C(=O)N2
Yield: 80 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 30d as starting materials to obtain (Z)—N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 30 (50 mg, yield 80%) as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Cl)[CH:34]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:29][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.06 (s, 3 H), 2.00–2.15 (m, 2 H), 2.50–3.20 (m, 5 H), 3.55–3.70 (m, 2 H), 4.90–5.00 (m, 1 H), 6.00–6.20 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.89 (d, J=9.0 Hz, 2 H), 7.25–7.52 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H), 10.41 (s, 1 H); MS (ES) m/z: 509.2 (MH+); HRMS Calcd. for C27H33N4O4S (MH+): 509.2223. Found: 509.2194.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([BH3-])#N.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCN
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CCNCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 3-nitrobenzaldehyde (127 mg, 0.84 mmol), N,N-dimethylethylenediamine (184 μL, 1.7 mmol), and HOAc (5 drops) in DCM (10 mL) was stirred at rt for 6 h and then heated to 40° C. for 1 hour. The reaction was cooled to 0° C., and sodium cyanoborohydride (360 mg, 1.7 mmol) was added in one portion. The reaction was stirred overnight at rt. After 16 h, the reaction mixture was washed with 4 N NaOH, dried over Na2SO4, and concentrated. The crude product was used in the next reaction without further purification. ES-LC/MS m/z=224 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][C:25]([O:26][CH3:27])=[C:20]([F:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ncc(B(O)O)cc1F
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ncc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)cc1F
Yield: 87.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 5-fluoro-6-methoxypyridine-3-boronic acid (159 mg, 0.94 mmol) were reacted. After purification the title compound (146 mg, 88% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.13(d, J=4.9 Hz, 1H), 8.45 (d, J=7.4 Hz, 1H), 8.29 (s, 1H), 8.11 (a d, J=13.8 Hz, 1H), 7.95(a d, J=7.2 Hz, 1H), 7.81 (a t, J=7.8 Hz, 1H), 4.03 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=354.
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(OCC2CCCO2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanyl methyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1500 g) was dissolved in methanol (10 mL). To this solution was added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was evaporated under reduced pressure and then water (3 mL) and methanol (3 mL) was added to the residue to give a finely divided suspension. This was neutralised (to pH 7) by the addition of 2N sodium hydroxide and then evaporated under reduced pressure to dryness. Water (3 mL) was then added to the residue and the resultant white suspension of solid was isolated by filtration under suction. The solid was washed with methanol (1 mL) and then air-dried under suction. The solid was then dried further to constant weight under vacuo at 50° C. (˜1 hour). This gave the title compound as a white solid (0.1130 g)
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)nc1-2

Procedure:
The title compound was prepared firom 7-methoxy-4,5-dihydronaphto[1,2-D][1,3]thiazol-2-amine hydrobromide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.3 mg) with purity >90%. MS (pos) m/z 455.1, 457.1.