Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1>>[C:33]([NH:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)(=[O:10])=[O:11])=[CH:27][CH:28]=1)(=[O:35])[CH3:34]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Product: COc1ccc(CN(Cc2ccc(NC(C)=O)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and N-(4-(chloromethyl)phenyl)acetamide. MS (M−H, 467.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.0 (s, 3H), 3.69 s, 3H), 4.23 (s, 4H), 6.78 (d, 2H, J=7.6 Hz), 6.98 (m, 4H), 7.41 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz), 8.09 (d, 2H, J=8 Hz), 9.90 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=[O:12])[NH:6]2.[CH2:15](I)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=[O:12])[NH:6]2)[CH:16]=[CH2:15]
Reactant: Cc1ccc(O)c2c1NC(=O)C2(C)C
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2c1C(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
8.21 g (42.99 mmol) of 2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one and 7.95 g (47.3 mmol) of allyl iodide were dissolved in 65 ml of N,N-dimethylformamide. After the addition of 12.0 g (87 mmol) of potassium carbonate, the mixture was stirred for 2 hours over a water bath at 70° C. After the reaction, the solvent was removed by evaporation under reduced pressure. Chloroform was added to the residue, and the mixture was washed with water, 2N sodium hydroxide aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 10:1 mixture of chloroform and ethyl acetate) and crystallized from n-hexane to obtain 5.67 g (yield, 57.1%) of colorless crystals of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[NH2:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(N(N)C(=O)c2ccc(F)cc2)cc1
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a stirred suspension of 5.0 gm (23.9 mMol) N-(4-fluorobenzoyl)-4-aminoaniline in 42 mL concentrated hydrochloric acid at 0° C. was added dropwise a solution of 1.65 gm (23.9 mMol) sodium nitrite in 30 mL water. The mixture was stirred for 10 minutes after the addition was complete and was then added dropwise to a solution of 19.6 gm (86.87 mMol) stannous chloride dihydrate in 40 mL concentrated hydrochloric acid at 0° C. The resultant white paste was stirred vigorously for 1 hour and was then filtered under vacuum. The solid which formed was then partitioned between ethyl acetate and 5N sodium hydroxide, the phases separated and the aqueous phase was extracted again with dichloromethane. The combined organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 3.8 gm (72%) of the title compound as a brown solid which is suitable for use in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:41]=[C:40](F)[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][C:37]=1[F:46]>CS(C)=O.CCOC(C)=O>[Br:35][C:36]1[C:37]([F:46])=[CH:38][C:39]([N+:43]([O-:45])=[O:44])=[C:40]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:41]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (12.8 g, 80 mmol) and 18-crown-6 (4.21 g, 15.94 mmol) in DMSO (100 ml) at 0° C. was added potassium tert-butoxide (1.0 M solution in THF) (80 ml, 80 mmol) and the reaction mixture was stirred at RT for 30 minutes. Next, 1-bromo-2,5-difluoro-4-nitrobenzene (19.4 g, 80 mmol) was added dropwise (in solution of 60 mL DMSO) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was triturated with methanol to give 2-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (21.3 g, 56.3 mmol, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, 1H), 7.34-7.40 (m, 1H), 7.21-7.34 (m, 2H), 2.23 (d, 3H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reaction time: 3 h

Procedure:
1.30 g (4.08 mmol) 2,2,2-trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone and 3.06 ml (6.13 mmol) 2 molar sodium hydroxide solution are dissolved in 20 ml THF at room temperature and stirred for 3 h. Then the mixture is concentrated by evaporation i.vac., diluted with water and extracted with tert.-butyl-methylether. The organic phase is washed with 50% sodium hydroxide solution and sat. NaCl solution, dried on sodium sulphate and concentrated by evaporation i.vac.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 238. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.52 (s, 1H), 8.22 (dd, J=7.3, 2.2 Hz, 1H), 7.84 (s, 1H), 7.43-7.29 (m, 2H), 4.89 (dd, J=10.1, 3.9 Hz, 1H), 4.57-4.37 (m, 1H), 4.35-4.20 (m, 1H), 4.17-3.94 (m, 1H), 3.79 (s, 3H), 3.29-3.17 (m, 1H), 2.40 (s, 3H), 2.19-2.07 (m, 1H), 1.92-1.77 (m, 1H), 1.76-1.66 (m, 4H). LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][C:37](Cl)=[O:38]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][C:37]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:38]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)Cc3ccc(Cl)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 18.4 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (25 ml) and 2,4-dichlorophenylacetyl chloride (0.56 g), the title compound (0.20 g) was obtained as a crystalline solid, m.p. 130-140° C., resolidifies, m.p. 180-182° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1Cl)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:8][C:2]=1[F:1])=[O:15]
Reactant: Nc1ccc(C2CC2)cc1F
Reactant: COC(=O)c1ccc2cncn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 2-fluoro-4-cyclopropyl aniline (395 mg, 2.61 mmol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (500 mg, 2.37 mmol) in THF under nitrogen at −70° C. (20 mL) was added lithium bis(trimethylsilyl) amide (4.98 mL, 1M solution, 4.98 mmol) dropwise. After stirring for 1 hour at −70° C. the reaction mixture was allowed to warm and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (150 mL), the organic extract dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane) to yield the title compound (573 mg, 60%). LCMS (Method B): RT=3.60 min, M+H+=326.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]([OH:43])[CH3:42]>>[OH:43][CH:41]([CH3:42])[CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC(O)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 39.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 23 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1.C(N(CC)CC)C.[Mn]([O-])(=O)(=O)=O.FC1C=CC=CN=1>CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1
Reactant: OCC[C@@H]1CCNC1
Reactant: Fc1ccccn1
Agent: O=[Mn](=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: OCC[C@@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
(S)-2-(Pyrrolidin-3-yl)ethanol 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) and triethylamine (17.36 mmol, 2.420 ml, 1.757 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. TLC (permanganate stain) suggested SM remained. Further 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) was added and heating continued for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with DCM—3% MeOH/DCM to afford (S)-2-(1-(pyridin-2-yl)pyrrolidin-3-yl)ethanol. 1H NMR (CDCl3) δ: 8.14 (d, 1H), 7.44 (m, 1H), 6.51 (m, 1H), 6.33 (d, 1H), 3.71 (m, 3H), 3.55 (m, 1H), 3.38 (m, 1H), 3.05 (m, 1H), 2.42 (m, 1H), 2.17 (m, 1H), 1.78 (m, 2H), 1.66 (m, 1H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:51][CH:50]([OH:52])[CH2:49]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: OC1CNC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CC(O)C2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with azetidin-3-ol (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O4 [(M+H)+] 721.3031, observed 721.3034.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH:20]=[N:10][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CCc1cc(C(N)=O)c(C)nc1OC
Product: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
In a round bottom flask under a nitrogen atmosphere, 5-ethyl-6-methoxy-2-methyl-nicotinamide (60 mg, 0.309 mmol) is treated with dimethylformamide dimethylacetal (0.5 mL). The resulting mixture is stirred at 100° C. for 1.25 hr to give a yellow solution. LC/MS shows the complete consumption of the starting material. The reaction mixture is evaporated to give N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methyl-nicotinamide directly as a cream solid that is used without purification. MS: m/e=250 (M+H); 1H NMR (CDCl3, δ, ppm): 8.57 (1H, s), 8.19 (1H, s), 5.77 (2H, s), 3.98 (3H, s), 3.19 (6H, s), 2.58 (3H, s), 2.56 (2H, q), 1.20 (3H, t).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
The product from step (ii) (30 g) was dissolved in dry DCM (200 ml). The solution was stirred at rt whilst N-bromosuccinimide (27 g) was added portion wise. The mixture was stirred at rt overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with DCM. The combined organic phase was washed with saturated NaHCO3 solution and brine. After concentration in vacuo, the residue was dissolved in EtOAc, washed with water, brine and dried. The solution was filtered through silica gel. The filtrate was concentrated in vacuo and dissolved in a mixture of diethyl ether and isohexane (1/1, 200 ml) to give the subtitle compound (26 g). The solvent was removed to give a residue, which was purified by column chromatography (EtOAc/isohexane), which afforded 2.5 g. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. mp 148-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3[N+](=O)[O-])ccc12
Yield: 12.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (121 mg, 0.57 mmol) and 2-nitro-benzyl bromide (118 mg, 0.69 mmol) to provide 466 (24 mg, 12% yield) as a white powder. LC-MS (M+H=347, obsd.=347). 1H NMR (400 MHz, DMSO-D6) δ 8.56 (d, J=6.6, 1H), 8.41 (d, J=3.1, 1H), 8.07 (dd, J=8.3, 15.1, 2H), 7.51 (dt, J=6.5, 14.0, 2H), 7.43 (d, J=1.9, 1H), 7.35 (dd, J=4.7, 7.9, 1H), 7.03 (d, J=7.6, 1H), 6.91 (dd, J=2.0, 8.7, 1H), 6.25 (s, 2H), 5.89 (s, 2H).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[C:31]2[CH:38]=[N:37][N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[C:32]=2[N:33]=[CH:34][N:35]=1)[C:25]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:26])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
A solution of trimethylaluminium (2M in hexane) (0.491 mL, 0.98 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (92 mg, 0.85 mmol) in toluene (5 mL) cooled to 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (420 mg, 0.85 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at 60° C. for 20 hours. The mixture was cooled and 1M citric acid (10 mL) added with vigorous stirring. The mixture was diluted with ethyl acetate (35 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (180 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.78-1.81 (2H, m), 2.20-2.30 (2H, m), 2.29 (3H, s), 3.71 (2H, t), 5.90-5.93 (1H, m), 7.45 (1H, dd), 7.51 (1H, dd), 7.99 (1H, dd), 8.07-8.08 (1H, m), 8.14 (1H, d), 8.42 (1H, s), 8.53 (1H, s), 8.60 (1H, dd), 8.62 (1H, s); m/z (ESI+) (M+H)+=568; HPLC tR=3.33 min.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 2-chlorophenylhydrazine hydrochloride (538 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (280 mg, 34%).
Reaction SMILES: Br[CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[Cl:12][C:11]1[C:6]([O:5][CH2:4][CH:3]([OH:13])[CH2:2][NH:17][CH:14]([CH3:16])[CH3:15])=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: OC(CBr)COc1nccnc1Cl
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1nccnc1Cl

Procedure:
53 g of 2-(3'-bromo-2'-hydroxy-propoxy)-3-chloropyrazine and 59 g of isopropylamine in 500 ml of methanol are boiled for 15 hours under reflux. The reaction mixture is then evaporated in a waterpump vacuum. The residue is partitioned between 2 N hydrochloric acid and ether. The hydrochloric acid phase is rendered alkaline with concentrated sodium hydroxide solution and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from ether. 3-Chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, melting point 99°-100° C., is thus obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.[I-].C[N+]1C=CC=CC=1Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:41][CH:42]([CH2:46][CH3:47])[C:43](O)=[O:44])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][CH:42]([CH2:46][CH3:47])[C:43]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)=[O:44])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 16.7 %

Procedure:
Triethylamine (1.99 ml), ethyl 4-aminophenylacetate hydrochloride (699 mg), and 1-methyl-2-chloropyridinium iodide (1.1 g) were added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)butanoic acid (1 g) in chloroform (30 ml), and the whole was heated under reflux for 2 hours under argon. The reaction mixture was concentrated under reduced pressure. After adding 1N HCl, the residue was extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 70 g, hexane/ethyl acetate=2/1) to give (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)butanamide (237 mg).