Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)CCOC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)OCCC(C)C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), isoamyl salicylate (416 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (110 mg, yield 56%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.CN(C=O)C.C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>C(OCC)(=O)C>[CH3:3][C:4]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:41](=[O:42])[CH2:40][C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)[CH2:20][CH2:21]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(CC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A mixture of 2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (240 mg, 0.79 mmol), DMF (5 ml) and triethylamine (0.22 ml, 1.58 mmol) was added p-tolylacetic acid (140 mg, 0.93 mmol) and WSCD (180 mg, 0.93 mmol) in this order followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water twice, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethylether to afford 1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-2-(4-tolyl)ethanone (172 mg, yield 64%) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]1)[CH2:7]2.[BH4-].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([OH:15])[CH:8]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:21][CH2:22]1)[CH2:7]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CN1CCN(c3ccccc3OC)CC1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)C(O)C(CN1CCN(c3ccccc3OC)CC1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
A suspension of 4.9 g of 2,3-dihydro-5,6-dimethoxy-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1H-inden-1-one, hydrochloride in 100 ml of methanol is cooled to 0° C. and treated with a solution of 1.52 g of sodium borohydride in 10 ml of water (the sodium borohydride is added dropwise). The mixture is stirred at room temperature overnight followed by the addition of an additional 1.52 g of sodium borohydride in 10 ml of water at 0° C. The mixture is stirred for an additional 2 hours at room temperature. The reaction mixture is chilled to 0° C. and treated with 30 ml of water. After 30 minutes at 0° C., the solvents are removed in vacuo, and the residue is distributed between dichloromethane and water. The organic layer is dried with sodium sulfate and evaporated in vacuo to a foamy residue (4.1 g). The residue is dissolved in a small amount of dichloromethane and chromatographed on a 150 g-Activity III neutral alumina column using ethyl acetate/hexane (3:1) in 50 ml fractions (a total of 500 ml). After evaporation of the combined fractions there is 2.7 g of residue. Trituration with pentane gives 2.28 g of an amorphous solid with indeterminant melting point. Crystallization from ethyl acetate/pentane yields 1.80 g of the title compound, melting point 109.5°-111.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[OH:26][CH2:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1>>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([N:32]3[C@H:28]([CH2:27][OH:26])[CH2:29][CH2:30][C:31]3=[O:33])=[CH:3][C:4]=2[F:25])=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCC(CO)N1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CC[C@H]4CO)cc3F)CC2)c(C)c1
Yield: 15 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 109 and 5-hydroxymethylpyrrolidin-2-one (230 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (133 mg) was obtained.
Reaction SMILES: C(N)C.[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCC.C(OCC)(=O)C>ClCCl.N#N>[CH3:10][O:9][C:7]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][CH:5]=[N:4]1)=[O:8]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: CCN
Agent: N#N
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1N=CO[C@H]1c1ccccc1
Yield: 0.1 %

Procedure:
27.5 mg (0.055 mmol) of bis(cyclohexylisocyanide)-gold tetrafluoroborate, 39.7 mg (0.056 mmol) of (R)-N-methyl-N-[2-(diethylamino)-ethyl]-1-[(S)-1',2bis(-ethylamine and 0.549 g (5.54 mmol) of methyl isocyano-acetate were dissolved in 5.5 ml of dry dichloromethane, and 0.642 g (6.05 mmol) of benzaldehyde was added thereto. The reaction mixture was reacted for 20 hours at 25° C in N2 atmosphere. After the solvent was concentrated, the residue formed was subjected to silica-gel column chromatography (solvent: hexane/ethyl acetate =1/2) to obtain 0.96 mg (84.6%) of trans-4-methoxycarbonyl-5- phenyl-2-oxazoline and 0.12 g (10.4%) of the corresponding cis-form.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[NH2:16][CH2:17][C:18]1([OH:25])[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:16][CH2:17][C:18]1([OH:25])[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:5])[CH3:2]
Reactant: CN1CCC(O)(CN)CC1
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCC1(O)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.5 %

Procedure:
A solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (3.717 g, 17.62 mmol) in dichloromethane (91 ml) in an ice-water bath was added with 4-aminomethyl-1-methyl-piperidin-4-ol (4 g, 19.38 mmol), N,N′-dimethylformamide (9.1 ml), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (8.751 g, 45.6 mmol) and 1-hydroxybenzotriazol (3,577 g, 26.5 mmol). Upon completion of the addition, the resulting mixture was stirred at room temperature overnight. The mixture was added with ice to quench the reaction, and washed with saturated potassium carbonate solution (10 ml×3) with brine (50 ml×3) The resulting mixture was partitioned and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-{[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-carbamoyl]-methyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.891 g) as a brown oil, which was used as such.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[N+:13]([O-])=O)C>C(O)(=O)C.[Fe]>[Br:12][C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][C:4](=[O:3])[NH:13]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(Br)cc2N1
Yield: 43 %

Procedure:
Using a procedure analogous to that described for the starting material in Example 57, ethyl(4-bromo-2-nitrophenyl)acetate (26 g, 90 mmol) was treated with iron in acetic acid. The product thus obtained was recystallised from ether/isohexanes to give 6-bromooxindole (8.2 g, 42%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 55 %

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with n-butylsulfonyl chloride to obtain the desired product. Yield: 55%. 1H-NMR (500 MHz, CDCl3): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H, J=1.5 Hz)5 5.65 (s, 1H, br), 3.06-3.031 (t, 2H, J=1.4 Hz), 1.75-1.71 (m, 2H), 1.38-1.36 (m, 2H), 0.87-0.86 (t, 3H, J=1.3 Hz); m/z=483 [M−1]−.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH:40]([CH3:42])[CH3:41])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH:40]([CH3:41])[CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CC(C)n1cc(C(=O)CCCCCBr)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C(C)C)c3ccccc23)CC1
Yield: 46.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.90 g) as starting compound and 6-bromo-1-(1-isopropyl-1 H-indol-3-yl)-1-hexanone (1.90 g) were reacted and treated in the same manner as in Example 199 to give 0.70 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-isopropyl-1H-indol-3-yl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[Cl:20])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24]O)[C:6]=2[C:5](C(OC)=O)=[CH:4][CH:3]=1.[CH2:30](N(CC)CC)C.CS(Cl)(=O)=O.[C:42](=[O:45])([O-])[O-:43].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]([O:43][CH3:30])=[O:45])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[Cl:20])[CH2:24][CH2:23][CH2:22][CH2:21][N:7]21
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)cc3Cl)n(CCCCO)c12
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a stirred solution of methyl 4-chloro-2-[(2-chloro-4-methoxyphenyl)amino]-1-(4-hydroxybutyl)-1H-benzimidazole-7-carboxylate (Reference example 169, 1.31 g, 2.98 mmol) and triethylamine (1.04 mL, 7.45 mmol) in tetrahydrofuran (15 mL) was added methanesulfonyl chloride (277 μL, 3.58 mol) at 0° C. After 15 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (30 mL) and potassium carbonate (1.24 g, 8.94 mmol) was added. After being stirred for 1 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (1.18 g, 2.81 mmol, 94%).
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[CH2:7]([C:11]1[N:12]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[NH:57][N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:13]([C:17]([O:19][CH:20]([O:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@@H:30]([O:36][N+:37]([O-:39])=[O:38])[CH2:31][O:32][N+:33]([O-:35])=[O:34])=[O:24])[CH3:21])=[O:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]>CC(O)C>[N+:37]([O:36][C@@H:30]([CH2:31][O:32][N+:33]([O-:35])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:23]([O:22][CH:20]([O:19][C:17]([C:13]1[N:12]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N-:57][N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:11]([CH2:7][CH2:8][CH2:9][CH3:10])=[N:15][C:14]=1[Cl:16])=[O:18])[CH3:21])=[O:24])([O-:39])=[O:38].[K+:5]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[n-]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (945 mg, 6.84 mmol) was added to a stirred solution of 1-[({[(5R)-5,6-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (250 mg, 0.34 mmol) in IPA (6.8 mL). The solution was stirred at 25° C. for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was redissolved in DCM (6 mL). Heptane was added until the compound began to precipitate. The solution was concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CD3CN) δ 7.72-7.68 (m, 1H), 7.40-7.33 (m, 2H), 7.33-7.28 (m, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 6.88-6.82 (m, 1H), 5.47 (s, 2H), 5.32 (ddd, J=13.0, 6.5, 2.5 Hz, 1H), 4.79 (dd, J=13.0, 2.5 Hz, 1H), 4.55 (dd, J=13.0, 6.5 Hz, 1H), 4.08 (td, J=6.5, 3.0 Hz, 2H), 1.71 (q, J=13.0, 7.7 Hz, 2H), 1.61 (hex, J=22.0, 14.5, 7.0 Hz, 4H), 1.50 (d, J=5.5 Hz, 3H) 1.49-1.37 (m, 2H), 1.35-1.26 (m, 2H), 0.85 (t, J=7.5 Hz, 3H); LCMS (M+H) found 731.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COC[C@@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.5 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide (32 mg, 0.061 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (300 μl, 4.44 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (1:1 dichloromethane/heptane) to afford 14 mg (59%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=399; 1H NMR (300 MHz, DMSO-d6) δ: 9.11 (s, 1H), 8.53 (d, J=8.6 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 4.30-4.46 (m, 1H), 4.18 (s, 3H), 3.53 (dd, J=9.6, 5.1 Hz, 1H), 3.47 (dd, J=9.6, 4.5 Hz, 1H), 3.27 (s, 3H), 1.31 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])(=O)C.[S:16]([NH2:26])(=[O:25])([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:17].CN(C1C=CC=CN=1)C.N1C=CC=CC=1>CCOC(C)=O>[Cl:15][C:6]1[CH:7]=[C:8]([S:11]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([S:16](=[O:25])(=[O:17])[NH2:26])=[CH:19][CH:20]=2)(=[O:12])=[O:13])[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 4-acetamido-3-chlorobenzenesulphonyl chloride (2.68 g, 10.0 mmol), sulphanilamide (2.06 g, 12.0 mmol), dimethylaminopyridine (1.22 g, 10.0 mmol) and pyridine (2.40 ml, 10.0 mmol) in EtOAc (150 ml) was stirred at ambient temperature for 3 days. The solution was washed with 1.0M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (22.1 ml) was added. The mixture was heated at reflux for 4 hours and then cooled to ambient temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralised to pH 7.0 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts washed with brine, dried and evaporated to give, as a solid, the title compound (2.34 g, 6.5 mmol). M.p. 197°-198°; NMR: 6.3 (s, 2H), 6.8 (d, 1H), 7.2 (s, 2H), 7.25 (d, 2H), 7.4 (dd, 2H), 7.55 (d, 1H), 7.65 (d, 2H); MS: 360.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27]C)[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[C:11]=2[CH:10]=1.O1CCCC1>C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([OH:27])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(N)=O)C(=O)NC3=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)CCn1c2ccc(O)cc2c2c3c(c(-c4c(Cl)cccc4Cl)cc21)C(=O)NC3=O
Yield: 59 %

Procedure:
Reaction of methyl ether (250) (80 mg, 0.17 mmol)) prepared as described in example 210 according to The procedure described in example 80, followed by chromatography on silica eluting with ethyl acetate then tetrahydrofuran and trituration from ethyl acetate, gave amide (258) (47 mg, 59%) as an orange powder, mp 327–329° C. 1H NMR δ [(CD3)2SO] 11.12 (br s, 1H), 9.39 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 7.61 (m, 3H), 7.51 (dd, J=8.8, 7.4 Hz, 1H), 7.38 (br s, 1H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 6.87 (br s, 1H), 4.65 (t, J=6.7 Hz, 2H), 2.55 (t, J=6.7 Hz, 2H). Found: C, 57.75; H, 3.83; N, 8.50. C23H15Cl2N3O4.3/4H2O requires: C, 57.33; H, 3.45; N, 8.72.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[CH3:27][N:28]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH2:45]([O:47][C:48]1[C:56]([O:57][CH3:58])=[CH:55][CH:54]=[CH:53][C:49]=1[CH2:50]CN)[CH3:46].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH2:45]([O:47][C:48]1[C:56]([O:57][CH3:58])=[CH:55][CH:54]=[CH:53][C:49]=1[CH2:50][N:28]([CH3:27])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)[CH2:15][C:14]=2[CH:16]=1)[CH3:46]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CCOc1c(CCN)cccc1OC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)cccc1OC
Yield: 37 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (155 mg, 37%) was prepared as a off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.15-10.13 (m, 2H), 8.40-8.35 (m, 1H), 8.00-7.92 (m, 1H), 7.54-7.42 (m, 1H), 7.25-7.20 (m, 1H), 7.13-6.68 (m, 2H), 6.66-6.61 (m, 1H), 5.11 (br s, 1H), 4.78-4.63 (m, 2H), 4.57-4.52 (m, 2H), 4.01-3.95 (m, 4H), 3.82-3.58 (m, 9H), 3.37-3.35 (m, 2H), 3.20-2.86 (m, 5H), 1.28-1.18 (m, 3H); MS (ESI) m/e 510 (M+H)+.
Reaction SMILES: B.CSC.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[N:26]([CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([F:46])[CH:33]=1)=[O:31])=[N+:27]=[N-:28].Cl>C1COCC1.C1(C)C=CC=CC=1>[N:26]([CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([F:46])[CH:33]=1)[OH:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c(F)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CSC
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Yield: 466.7 %

Procedure:
Borane-dimethylsulphide solution in THF (2M, 0.03 mL) was added to a solution of (R)-2-methyl-CBS-oxazaborolidine in toluene (1M, 0.06 mL) at 0° C. with stirring. The reaction mixture was stirred for 15 min prior to the dropwise addition of a solution of 2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (100 mg) in THF. Further Borane-dimethylsulphide in THF (2M, 0.03 mL) was added dropwise and the reaction mixture stirred at 0° C. for 2 h. 2M HCl(aq) (2 mL) was added dropwise and the reaction mixture stirred for 10 min prior to partitioning the reaction mixture between ether and water. The organic phase was washed twice with 2M HCl(aq), three times with sat. NaHCO3(aq), water and brine. The organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with DCM to give the title compound (470 mg). LCMS RT=3.36 min.