Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2([C:32](O)=[O:33])[CH2:31][CH2:30]2)=[O:28])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]2([C:32]([NH:18][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[C:10]5[CH:17]=[CH:16][NH:15][C:11]=5[N:12]=[CH:13][N:14]=4)=[C:2]([F:1])[CH:3]=3)=[O:33])[CH2:31][CH2:30]2)=[O:28])=[CH:24][CH:25]=1
Reactant: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4[nH]ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine (0.07 g, 0.29 mmol, 1.0 eq.), 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.105 g, 0.32 mmol), HATU (0.304 g, 0.58 mmol), triethylamine (0.13 ml, 0.87 mmol), and anhydrous DMF (3 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 ml) and extracted with CHCl3 (3×). The combined CHCl3 extractions were washed with H2O (1×), sat'd NaHCO3 (2×), 10% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting crude residue was purified by HPLC to yield N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-cyclopropane-1,1-dicarboxamide as a white solid (0.011 g, 9.0% yield). 1H NMR (400 MHz, DMSO): 9.59 (bs, 1H), 8.47 (s, 1H), 7.85 (m, 2H), 7.65 (m, 3H), 7.48 (d, 1H), 7.36 (t, 1H), 7.19 (d, 1H), 7.15 (t, 3H), 1.44 (s, 5H); MS (ESI) for C23H17F2N5O3: 450 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[CH:7][CH:6]=2)#[N:2].[Br:22]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:14][C:8]1[C:9]([O:12][CH3:13])=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]([C:1]#[N:2])=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)ccc2c1cc(C#N)n2C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(CBr)ccc2c1cc(C#N)n2C(=O)OC(C)(C)C
Yield: 119 %

Procedure:
To a stirred solution of 561 mg of tert-butyl 2-cyano-4-methoxy-5-methyl-1H-indole-1-carboxylate (1.96 mmol) in carbon tetrachloride (9 mL) was added 349 mg of N-bromosuccinimide (1.96 mmol) and 64 mg of AIBN (0.39 mmol). The mixture was refluxed for 1 h, then cooled and concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 852 mg of crude tert-butyl 5-(bromomethyl)-2-cyano-4-methoxy-1H-indole-1-carboxylate that was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[O:26][N:25]=[C:24]([C:27]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[CH:23]=1)(=[O:21])[CH3:20]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 24.6 %

Procedure:
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (106 mg, 0.408 mmol) and 5-acetylisoxazole-3-carboxylic acid (76 mg, 0.490 mmol). The product was purified by Flash-chromatography. Yield 24.6%. 1H-NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.63 (s, 3H), 3.78-3.88 (m, 1H), 3.91-4.00 (m, 1H), 4.59-4.69 (m, 1H), 6.63 (d, 1H), 7.29 (s, 1H), 7.50 (s, UT), 7.67-7.77 (m, 2H), 7.82 (dd, 1H), 8.05 (d, 1H).
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C@@H:12](O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[Br:1]/[CH:2]=[C:3]1/[C@H:11]2[C@:7]([CH3:15])([CH2:6][CH2:5][CH2:4]/1)/[C:8](=[CH:12]/[CH3:13])/[CH2:9][CH2:10]2
Reactant: C[C@H](O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C=C1\CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 0 °C
Yield: 44.5 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanol (Compound 18: 52.4 mg, 0.1918 mmol) and triphenylphosphine (126 mg, 0.4795 mmol) in tetrahydrofuran (0.3 ml) was cooled in an ice bath, and azodicarboxylic acid diethyl ester (2.2 M in toluene, 223.4 μl, 0.4915 mmol) was added dropwise thereto. The reaction mixture was stirred in the ice bath for 10 minutes and at room temperature for 21 hours, and then evaporated under reduced pressure. The obtained crude product was purified by flash column chromatography to obtain (1E,3aR,4E,7aS)-4-(bromomethylene)-1-ethylidene-octahydro-7a-methyl-1H-indene (21.8 mg, 44.6%).
Reaction SMILES: [C:1]([N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:34](Cl)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:43]1[CH:50]=[CH:49][C:46]([O:47][CH3:48])=[CH:45][CH:44]=1)[C:35]1[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH3:48][O:47][C:46]1[CH:45]=[CH:44][C:43]([C:34]([O:20][CH2:19][C@H:18]2[O:21][C@@H:14]([N:13]3[C:22]4[N:23]=[C:7]([N:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:8][C:9](=[O:24])[C:10]=4[N:11]=[CH:12]3)[CH2:15][C@@H:16]2[OH:17])([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:35]2[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=2)=[CH:50][CH:49]=1
Reactant: CCCCCCCCCN(C(=O)C(C)C)c1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCN(C(=O)C(C)C)c1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)O2)c(=O)[nH]1

Procedure:
Compound 118 was prepared from compound 117 by following the procedure of example 107 utilizing compound 117 (2.2 g, 4.75 mmole), DMTCl (1.69 g, 5 mmole), dry TEA (1.01 g, 10 mmole) and dry pyridine (70 ml). The crude compound was purified using flash chromatography and methylene chloride/methanol/TEA as the eluent. 2 g (55%) of pure product was obtained as a foam.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21]C(O)=O)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C(C1C=CC(OCC2C3=NC=C(CCC4[NH:57][N:56]=[N:55][N:54]=4)C(=O)N3C=CC=2)=C(CCC)C=1O)(=O)C>>[CH3:29][CH2:28][CH2:27][C:6]1[C:5]([OH:30])=[C:4]([C:1]([CH3:2])=[O:3])[CH:26]=[CH:25][C:7]=1[O:8][CH2:9][C:10]1[C:15]2=[N:16][CH:17]=[C:18]([C:21]3[N:57]=[N:56][NH:55][N:54]=3)[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCc4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2cccn3c(=O)c(CC(=O)O)cnc23)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccn3c(=O)c(-c4nn[nH]n4)cnc23)ccc(C(C)=O)c1O

Procedure:
Furthermore, [9-(4-acetyl-3-hydroxy-2-n-propylphenoxymethyl)-4-oxo-pyrido[1,2-a]pyrimidin-3-yl]acetic acid (to be referred to as AS-148) and 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-[2-(1H-tetrazol-5-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (to be referred to as AS-163) could not be formed into an aqueous solution as AS-35 could not. The present inventors confirmed the above finding by their own experiments.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28]OS(C)(=O)=O)[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[CH3:34][NH2:35].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C@H:18]([CH2:28][NH:35][CH3:34])[CH2:17]2)=[O:14])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COS(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 32 h
Yield: 39 %

Procedure:
The mixture of tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (197 mg, 0.41 mmol, step 1 of Example 17) and 40% monomethylamine aqueous solution (3 mL) in tetrahydrofuran (2 mL) was stirred at 80° C. for 32 h. After cooling to room temperature, the mixture was added to saturated sodium hydrogencarbonate aqueous solution. The organic phase was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of NH gel eluting with n-hexane/ethyl acetate (4:1 to 2:1) to give 66 mg (39%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[CH:8](O)=[O:9]>>[CH:8]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:9]
Reactant: Cc1cc(N)no1
Reactant: O=CO
Product: Cc1cc(NC=O)no1
Yield: 93.8 %

Procedure:
To 3-amino-5-methylisoxazole (10.0 g), 99% formic acid (47.0 g) is added, and the resultant mixture is refluxed for 1 hour with stirring. The reaction mixture is evaporated under reduced pressure to remove the formic acid. The residue is mixed with icy water (50 ml), and the precipitated crystals are filtered. The crystals are washed with water and dried under reduced pressure to give 3-formylamino-5-methylisoxazole (12.06 g). This substance is recrystallized from methanol to give crystals melting at 130.5° to 131° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]2[OH:38])[C@@:30]2([CH:39]=[CH2:40])[C@H:21]1[C:22]1[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=1[CH2:28][CH2:29]2>>[N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@@:30]3([CH:39]=[CH2:40])[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=2[CH2:28][CH2:29]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with piperidine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 34 mg of mixture 30b yields 40 mg of amine 34b as a colorless foam (GC-MS: m/z theor.: 465, pract.: 465).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2cccc(N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a mixture of 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (100 mg) in acetic acid (4 mL) was added a solution of SnCl2.2H2O (10 eq) in 1.5 mL of concentrated HCl. The reaction was stirred at room temperature 12 h. The excess acid was partially removed in vacuo, and the reaction mixture was then poured into a flask (250 mL) and was neutralized with saturated NaHCO3 solution at 0° C. The pH was brought up to pH 9 by adding solid NaHCO3. The resulting aqueous mixture was diluted with EtOAc, and the Tin-by product was removed by filtering through a pad of diatomaceous earth. The pad was rinsed with EtOAc and the combined filtrates were partitioned in a separatory funnel. The aqueous layer was extracted with EtOAc two times. The combined organics were dried over MgSO4, filtered and concentrated to give the desired 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (100%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[C:2]1([O:1][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][NH2:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.38 g (6.59 mmol) of 3-phenoxyphenylacetonitrile and 1.57 g (6.59 mmol) of cobalt(II) chloride hexahydrate are dissolved in 25 ml of methanol. The solution is cooled with an iced water bath and 1.74 g (46 mmol) of sodium borohydride are added in portions. The reaction mixture is stirred overnight at ambient temperature. It is filtered on paper and rinsed with twice 25 ml of methanol. The filtrate is concentrated under reduced pressure and the residue is taken up in 50 ml of aqueous hydrochloric acid (1N) and 25 ml of ether. After distinct phases have separated out they are separated. The aqueous phase is washed with three times 25 ml of ether. The aqueous phase is rendered alkaline with 10 ml of aqueous 36% sodium hydroxide and extracted with three times 50 ml of dichloromethane. The extracts are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate and the filtrate is concentrated under reduced pressure. This gives 0.67 g of product in the form of a brown-orange oil, which is used as it is in the following step.
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[CH:9]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([C:16]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: COC(=O)C(C)N
Agent: Cl
Product: CC(NC(=O)C1CCCCCC1)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 4A using 20 g (143 mmol) of D,L-alanine methyl ester hydrochloride and 23.02 g (143 mmol) of cycloheptanoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:9][C:10]([F:17])([F:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([F:17])([F:16])[F:9])=[N:6][CH:7]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: FC(F)(F)[C@@H]1CCCN1c1ncc(Br)cn1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
A flask was charged with 5-bromo-2-chloropyrimidine (36.62 g, 189 mmol), (S)-2-(trifluoromethyl)pyrrolidine (34.2 g, 246 mmol), potassium carbonate (39.2 g, 284 mmol)) and t-amyl alcohol (189 mL). The reaction mixture was stirred at 85° C. for 72 hours. The reaction mixture was then filtered over Celite®, washed with CH2Cl2 (2×) and concentrated in vacuo. The crude residue was redissolved in CH2Cl2 and washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give crystalline solids. The solids were washed with cold water (3×) and triturated with toluene to give the title product as pale orange crystals, 43.4 g (147 mmol, 77%); 1H NMR (300 MHz, DMSO-d6)_8.58 (s, 2H), 5.06-4.83 (m, 1H), 3.71-3.44 (m, 2H), 10 2.30-1.89 (m, 4H); m/z found [M+H]+=295.99.
Reaction SMILES: [C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:31](=O)(O)[O-].[Na+]>>[C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:8])[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CC(C)(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1

Procedure:
Treat the secondary amine (3) (249 mg, 0.57 mmol) with 1M hydrochloric acid (20 ml) and heat the reaction to 50° C. for 30 minutes. Cool the reaction and pour into saturated sodium bicarbonate (200 ml). Extract the reaction with chloroform (3×150 ml). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under vacuum. Purify the residue by radial chromatography (2% to 4% to 8% to 15% methanol/chloroform, 4 mm plate) four times to provide the title compound (105 mg) as the free base. Treat this with ethereal hydrogen chloride, filter, and dry the solid under high vacuum over phosphorous pentoxide to provide the hydrochloride salt of the Formula I (48 mg), m.p. 153° C. dec.; [α]D20 =30° (c=1.04, H2O)
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(O)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 26.5 %

Procedure:
A mixture of 4-methoxy-2-nitrobenzonitrile (820 mg, 4.6 mmol) and pyridine hydrochloride (755 mg, 4.6 mmol) was heated at 200° C. under N2 for 18 hours. Upon completion, the reaction was cooled to room temperature, washed with brine and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (1:1 Hexane:EtOAc) to provide 4-hydroxy-2-nitrobenzonitrile (200 mg, 26%). 1H NMR (400 MHz, MeOD) δ 7.24 (dd, J=8.6, 2.4 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:36])[CH3:35])[CH:5]=[CH:6][C:7]=1[C:8]1[NH:30][C:11]2=[N:12][CH:13]=[C:14]([Cl:29])[C:15]([C:16]3[S:20][C:19]([C:21]4([O:25]COC)[CH2:24][CH2:23][CH2:22]4)=[N:18][CH:17]=3)=[C:10]2[CH:9]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:35])[CH3:36])[CH:5]=[CH:6][C:7]=1[C:8]1[NH:30][C:11]2=[N:12][CH:13]=[C:14]([Cl:29])[C:15]([C:16]3[S:20][C:19]([C:21]4([OH:25])[CH2:24][CH2:23][CH2:22]4)=[N:18][CH:17]=3)=[C:10]2[CH:9]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5Cl)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN(C)CC(=O)Nc1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(3-chloro-4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-2-(dimethylamino)acetamide (Example 61C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (400 MHz, DMSO-d6) ppm 12.45 (s, 1H) 10.10 (s, 1H) 8.38 (s, 1H) 8.23 (s, 1H) 8.06 (d, 1H) 7.73 (m, 2H) 6.89 (s, 1H) 6.68 (s, 1H) 3.12 (s, 2H) 2.61 (m, 2H) 2.40 (m, 2H) 2.29 (s, 6H) 1.97 (m, 2H); MS ESI(+) m/z 518.0 [M+H]+.
Reaction SMILES: N1C(Cl)=NC(Cl)=N[C:2]=1Cl.[Na].[NH2:11][C:12]1[CH:17]=[C:16](N)[CH:15]=[CH:14][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:2])=[CH:14][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na]
Product: Cc1ccc(N)c(S(=O)(=O)O)c1

Procedure:
31.4 Parts of 8-amino-naphthol-3,6-disulphonic acid are condensed with cyanuric chloride at 0° C. and pH 1 to 2. To the suspension of the primary condensation product is added an aqueous solution of 21 parts of the sodium salt of 2,4-diaminobenzenesulphonic acid and condensation is effected at a pH of 4 to 5. When the condensation is complete, the secondary condensation product is coupled at pH 6 to 6.5 with the diazo compound obtained from 18.7 parts of 2-amino-5-methylbenzenesulphonic acid. The red dye solution is then added to a suspension of 2-(2'-sulphophenylamino)-4,6-difluoro-1,3,5-triazine prepared by condensing 17.3 parts of 2-aminobenzenesulphonic acid with 13.5 parts of 2,4,6-trifluoro-1,3,5-triazine at 0° C. The hydrogen fluoride liberated during the condensation is neutralised continously by adding sodium carbonate solution. When the condensation is complete, the reaction product is isolated in the form of a red powder by evaporating the water under reduced pressure. The dye colours cellulose fibres in fast, bluish red shades.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)([CH3:18])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.[OH-:30].[Na+].Cl>C(O)C.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([NH:19][C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:28])=[O:30])[CH:22]=3)=[O:29])([CH3:18])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1
Reactant: [OH-]
Reactant: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(C(N)=O)c1
Temperature: 0 °C
Yield: 30.3 %

Procedure:
To a solution of N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-cyanoisonicotinamide (300 mg, 724 umol) in ethanol (20 mL) at room temperature, was added a solution of sodium hydroxide (275 mg, 7.06 mmol) in water (6 mL). The reaction was microwaved at 80° C. for five minutes, and upon completion was cooled 0° C., neutralized with 1N HCl, concentrated and purified by flash chromatography (1/9 methanol/dichloromethane). The purified product was washed with hot ethanol and the solid was collected by vacuum filtration and dried under vacuum at 50° C. to yield N4-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)pyridine-2,4-dicarboxamide (95 mg, 29%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.50 (s, 6 H), 4.38 (s, 2H), 6.62 (d, J=0.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 1 H), 7.47 (t, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.86 (dd, J=5.2 Hz, 1H), 8.19 (s, 1H), 8.35 (s, 1H), 8.39 (s, 1H), 8.69 (s, 1H), 8.73 (dd, J=4.8 Hz, 1H), 10.99 (s, 1H). MS 433 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[Cl:23][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Cl)c1N1CCNCC1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 5.47 mmol) was dissolved in trifluoroacetic acid (5.0 mL) and CH2Cl2 (5.0 mL) and allowed to stir for 2 h. The reaction mixture was concentrated, diluted with EtOAc, and washed with saturated aq. NaHCO3. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 100% CH2Cl2) to afford 1-(2-chloro-6-nitro-phenyl)-piperazine (1.26 g, 95%). MS (electrospray): exact mass calculated for C10H12ClN3O2, 241.1; m/z found, 242.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.54 (dd, J=8.2, 1.6 Hz, 1H), 7.49 (dd, J=8.2, 1.6 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 3.08 (br s, 4H), 2.99 (br s, 4H), 2.07-2.12 (m, 1H).