Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:15]1[CH:20]=[N:19][CH:18]=[C:17]([CH:16]=1)[CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cncc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (158 μL, 1.819 mmol) in methylene chloride (10 mL) was placed in a two-necked flask at −78° C., followed by the addition of dimethyl sulfoxide (129 μL, 1.819 mmol). Stirring was continued for 20 min, followed by addition of (5-tert-butylpyridin-3-yl)methanol (0.2 g, 1.21 mmol) in methylene chloride (10 mL). After the mixture was stirred at −78° C. for additional 20 min, triethylamine (0.59 mL, 4.24 mmol) was added. The cooling bath was removed and the suspension was allowed to warm to room temperature. Water (50 mL) was added, the yellow organic layer was separated, and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic solution was dried and concentrated to give 5-tert-butylnicotinaldehyde as an orange-yellow liquid which was used directly for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:31][C@H:30]([C:29]([O:28][CH3:27])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:10]
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Methyl-4′-nitrobiphenyl-4-carboxylic acid (0.50 g, 1.0 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.25 mL, 0.29 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.39 g, 2.3 mmol), methylene chloride (10 mL), and triethylamine (1.08 mL, 7.75 mmol). The resulting solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (50% EtOAc in hexanes). This yielded 0.653 g (91%) of the title compound. LC/MS m/z 370.9 (MH+), retention time 3.29 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 2.55 (s, 3H), 3.78 (s, 3H), 4.71-4.78 (m, 1H), 6.33 (d, 1H), 7.42-7.52 (m, 3H), 7.82 (d, 2H), 8.26 (d, 2H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[C:30]([S:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.OP(O)(O)=O>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:32][S:31][C:30]1[C:21]([NH:20][C:3](=[O:5])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: CCCCCCCCC(Br)C(=O)O
Reactant: CSc1ccc2ncccc2c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCC(Br)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-bromodecanoic acid (184 mg, 0.73 mmol) in CH2Cl2 (3.0 ml) was injected by syringe oxalyl chloride (0.06 ml, 105 mol %) and then DMF (1 drop). After stirring at room temperature for 1 hour, N-methyl morpoline (0.24 ml, 300 mol %) was added. To this mixture was injected a solution of 5-amino-6-methylthioquinoline (139 mg, 100 mol%) in CH2Cl2 (2.0 ml). After stirring at room temperature for an additional 30 min. the reaction mixture was diluted with CH2Cl2 (30 ml), poured over 1.0M H3PO4 (100 ml), and extracted with CH2Cl2 (3×30 ml). The combined extracts were dried (Na2SO4), evaporated, and chromatographed using 1% triethylamine: ethyl acetate as eluants to give the title compound (192 mg, 62% yield).
Reaction SMILES: O=[C:2]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:3]=O.[F:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[N:17]([NH2:22])[C:18]([NH2:21])=[N:19][N:20]=2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[N:17]3[N:22]=[CH:3][C:2]([C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)=[N:21][C:18]3=[N:19][N:20]=2)=[CH:13][CH:12]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: O=CC(=O)c1cccs1
Product: Fc1ccc(Cc2nnc3nc(-c4cccs4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-thiophen-2-yl-acetaldehyde and 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine to provide 3-(4-fluoro-benzyl)-7-thiophen-2-yl-[1,2,4]triazolo[4,3-b][1,2,4]triazine and 3-(4-fluoro-benzyl)-6-thiophen-2-yl-[1,2,4 ][triazolo 1,2,4,-b][1,2,4]triazine (example 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](OC4C=CC=CC=4)=[O:23])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[NH2:32][NH2:33]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:32][NH2:33])=[CH:17][N:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cn3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cn3)CC2)cc1

Procedure:
A mixture of the product of part (iii) (2.8 g, 6.9 mmole) and hydrazine hydrate (7.5 ml, 150 mmole) in 1,4-dioxane (50 ml) was heated under reflux for 1.5 hours. The cooled mixture was filtered to provide a solid which was washed with ether to yield the desired product, m.p. 280°-282° (2.0 g, 85%), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cc4ccccc4s3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), benzo[b]thien-2-ylboronic acid (100 mg, 0.557 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(benzo[b]thiophen-2-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.8-7.91 (m, 3H), 7.78 (s, 2H), 7.61-7.7 (t, 1H), 7.3-7.4 (m, 4H), 7.18 (d, 1H), 7.02 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.81 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.18 (s, 3H), 3.01 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9]O)[CH:4]=[N:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)(Cl)Cl>[Br:31][CH2:9][CH2:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc(CCCO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Cn1cc(CCCBr)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Dissolve 3-(1-methyl-1H-pyrazol-4-yl)-propan-1-ol (0.250 g, 1.783 mmol) in dry chloroform (15 mL). Add PS-triphenylphosphine resin (1.824 g, 3.923 mmol) and carbon tetrabromide (0.650 g, 1.961 mmol). Stir at room temperature under nitrogen for 3 hr. Filter reaction over paper with DCM. Concentrate filtrate in vacuo to obtain the title preparation (0.362 g, 100% yield). GC-MS (m/z): 202/204(M+), 95.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=2)=[CH:27][CH:28]=1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)o1

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (50 mg, 0.27 mmol), 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (81.5 mg, 0.27 mmol)) and N,N-diisopropylethylamine (71 L, 0.41 mmol) in dioxane (2.8 mL) was heated at 160° C. in a microwave oven for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless foam (31 mg, 26%).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:22][CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(CBr)c1cccnc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1c(OCC(=O)c2cccnc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (600 mg, 2 mmol) (HBr salt) was added to a mixture of 2-amino-3-nitrophenol (300 mg, 2 mmol) and potassium carbonate (400 mg, 3 mmol) in acetone (30 mL, 400 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, was diluted with water, and was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-(2-amino-3-nitrophenoxy)-1-pyridin-3-ylethanone (0.35 g, 60%). LCMS calculated for C13H12N3O4 (M+H)+: m/z=274.1. found: 274.1.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1O)[N:10](CC1C=CC=CC=1)[CH:9]=[CH:8][C:7]2=O)(=O)C.C(=O)([O-])[O-:24].[K+].[K+].BrCC=C.O>CN(C)C=O>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]1=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc2c(=O)ccn(Cc3ccccc3)c2cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: O
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 1 h
Yield: 198.7 %

Procedure:
A mixture of 6-acetyl-7-hydroxy-1-phenylmethyl-4(1H)-quinolinone (6.3 g, 21.5 mmol), anhydrous potassium carbon- ate (2.97 g, 21.5 mmol) and 3-bromopropene (2.86 g, 2.36 mmol) was stirred at room temperature in dry dimethylformamide (100 ml) for 18 hours. The mixture was poured into a large excess of water and was stirred rapidly for 1 hour. The solid produced was filtered off and washed well with water. The yellow solid was dried to give the required quino- lone as a yellow powder 6.2 g (87%) mp 139°-140°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=1)=[O:4].[CH2:17]([NH:19][C:20]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[S:21])[CH3:18]>>[BrH:1].[CH2:17]([N:19]1[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:18]
Reactant: Cc1cc(C(=O)CBr)cc(S(N)(=O)=O)c1C
Reactant: CCNC(=S)NCC(C)C
Product: Br
Product: CCN1C(=NCC(C)C)SCC1(O)c1cc(C)c(C)c(S(N)(=O)=O)c1

Procedure:
was obtained in a manner analogous to the method described in Example 6 from 3.1 g of 2-bromo-3',4'-dimethyl-5'-sulfamoylacetophenone and 1.7 g of 1-ethyl-3-isobutyl-thiourea. M.p. 145° C (decomposition).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:6]1[CH:5]=[C:4]2[C:9](=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1)[N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
1-(1,1-dimethylethyl) 7-methyl 2,3-dihydro-1H-indole-1,7-dicarboxylate (3.1 g, 11.2 mmol) and N-bromosuccinimide (2.0 g, 11.2 mmol) were dissolved in dry dichloromethane (100 mL) and stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction was partitioned with sodium hydroxide solution (2 M), separated and washed with more sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a gummy red solid (3.55 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27](Cl)=[O:28])=[C:20]2[N:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:14][C:13]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[N:10]=[CH:11][CH:12]=3)=[O:28])=[C:20]2[N:19]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Nc1ccnn1-c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccnn1-c1cccc(C(F)(F)F)c1)c1cnn2ccc(Cl)nc12
Temperature: 50 °C
Yield: 58.7 %

Procedure:
To a stirred solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (200 mg, 0.88 mmol) in dichloromethane (30 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (215 mg, 1.0 mmol) and diisopropylethylamine (130 mg, 1.0 mmol). The mixture was heated to 50° C. overnight. After cooling to room temperature, the mixture was concentrated to afford crude 5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, yield 58%), which was used for the next step without further purification. MS (ESI) m/z: 407.2
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[C:12]([CH2:16][CH2:17][NH:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:24]=1[CH3:25])=[CH:11]2>ClCCl.ClCCl.CO>[F:5][C:6]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:16][CH2:17][N:18]([CH2:19][C:20]4[N:21]=[CH:22][N:23]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[C:24]=4[CH3:25])[C:1](=[O:2])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(CNCCc2cc3cccc(F)c3n2C)ncn1S(=O)(=O)N(C)C
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of phosgene (12.5% v/v in toluene; 4 ml) in dichloromethane (4 ml) was added a solution of 4-[[[2-(7-fluoro-1-methyl-1H-indol-2-yl)ethyl]amino]methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (100 mg) in dichloromethane (4 ml), and the resulting mixture was stirred for 1 h. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (5 ml). Aluminium chloride (68 mg) was added, and the mixture was heated at reflux for 3 h. The cooled mixture was then poured into 2M sodium hydroxide solution (80 ml) and extracted with dichloromethane (2×50 ml). The combined, dried organic extracts were evaporated in vacuo to leave a solid which was dissolved in dichloromethane:methanol (1:1; 50 ml) and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave a solid (21 mg) which was triturated with ether to give the title compound (14 mg), m.p. 162°-166°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21]C(OC(C)C)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][Cl:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (11.3 mL, 1.0 M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.C(OC([NH:50][CH2:51][CH2:52][NH2:53])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:50][CH2:51][CH2:52][NH2:53])=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and N-tert.-butyloxycarbonyl-ethylenediamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:7]1[C:8](=[O:11])[NH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(=O)[nH]c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1c[nH]c(=O)c(Br)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of Example 288c (0.671 g, 3.87 mmol) and sodium acetate (0.318 g, 3.87 mmol) in acetic acid (8.50 mL) was added bromine (0.201 mL, 3.91 mmol) dropwise as a solution in acetic acid (1.7 mL). The reaction mixture was stirred at 40° C. for 3 hours. Bromine (0.05 mL) was added, and the reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with 100 mL of 10% aqueous sodium thiosulfate. The resulting suspension was filtered, and the solid collected and dried for 16 hours to provide the title compound (0.64 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NC2CCN(C)CC2)cc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
3-Nitro-4-methoxybenzoic acid (Aldrich; 300 mg, 1.52 mmol), 1-methyl-4-aminopiperidine (Fluorochem; 174 mg, 1.52 mmol), HATU (868 mg, 2.28 mmol) and DIPEA (796 uL, 4.56 mmol) were stirred in DMF (6 mL) at room temperature for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol and then eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated to give the title compound as an orange solid (341 mg, 76.4%).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[CH:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH2:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccoc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 251A (0.028 g, 0.064 mmol) in tetrahydrofuran (1.3 mL) and methanol (0.005 mL, 0.128 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.050 mL, 0.100 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.79 (m, 2 H) 6.03 (t, J=6.80 Hz, 1 H) 6.65 (s, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.27 (m, 3 H) 7.54 (m, 2 H) 7.68 (m, 3 H) 8.08 (d, J=7.72 Hz, 1 H) 16.26 (s, 1 H). MS (ESI−) m/z 435 (M−H)−.