Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12)[NH2:13].C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12
Reactant: COc1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1OCCN1CCOCC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Ethyl chlorooxoacetate (0.11 mL, 0.95 mmol) was added to a solution of the amine 139 (313 mg, 0.63 mmol) and triethylamine (0.18 mL, 1.26 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 5% MeOH/95% DCM to 7% MeOH/93% DCM) to afford title compound 140 as a yellow solid (178 mg, 47% yield). MS (m/z): 596.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:6][C@H:7]2[CH3:12].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:13][O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16])[N:6]([C:31](=[O:32])[CH2:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[Cl:22])[C@H:7]2[CH3:12]
Reactant: O=C(O)Cc1c(F)cccc1Cl
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Reaction time: 3 h
Yield: 81.6 %

Procedure:
Dissolve (1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.85 g, 4.99 mmol) and 2-chloro-6-fluorophenylacetic acid (1.04 g, 5.49 mmol) in dichloromethane (50 mL). Add 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.85 g, 7.49 mmol) and diisopropylethylamine (1.3 mL, 7.49 mmol) at rt. Stir 3 hours. Add water and extract with dichloromethane three times. Combine the dichloromethane extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give the title compound as a white foam (2.2 g, 4.07 mmol). MS (m/z): 540.2 (M+1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16][CH:17]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)[CH2:18][CH2:19][CH2:20][NH:21]C)[CH:9]=1.[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(O)(=O)C(O)=O>CS(C)=O.O.O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)[O:16][C:10]1[CH:9]=[C:8]([Cl:7])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CNCCCC(Oc1cc(Cl)ccc1C#N)c1ccoc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1OC(CCCN)c1ccoc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a tetrahydrofuran solution of the iodo intermediate from Example 27 step (e) (30 ml, 1.42 mmol), was added dropwise a solution of sodium azide (0.28 g, 4.26 mmol) in dimethyl sulphoxide (5 ml). The reaction was then stirred for 22hat room temperature. The solution was then treated with triphenylphosphine (1.12 g, 4.26 mmol) and water (5 ml) and stirred for 24hat room temperature. Aqueous saturated sodium bicarbonate solution (30 ml) was added and the mixture extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (2×30 ml), dried (sodium sulphate) and evaporated. The residue was dissolved in methanol, applied to a CC SCX resin, washed with methanol (200 ml) and then eluted with 7N ammonia in methanol (100 ml). The solvent was removed in vacuo and the residue-chromatographed on flash silica, eluting with 7% 7N ammonia in methanol in dichloromethane. The product was dissolved in methanol, treated with one equivalent of oxalic acid, stirred for ten minutes and then the solvent was removed in vacuo. The solid residue was recrystallised from isopropanol to give the title compound as a white solid (0.26 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>C1(C)C(C)=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: N#Cc1ccccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: Brc1ccccc1-c1nnn[nH]1
Reaction time: 2 h
Yield: 76 %

Procedure:
A 64 g (350 mmol) sample of 2-bromobenzonitrile (Aldrich) was dissolved in 650 mL of xylene and treated with 22.75 g (350 mmol) of sodium azide and 95 mL (350 mmol) of tributyltin chloride at reflux for 48 h. The reaction was filtered; the filtrate was treated with 50 mL of anhydrous tetrahydrofuran (THF) and 20 g (550 mmol) of hydrogen chloride. The reaction was stirred for 2 h; filtration gave 59.6 g (76%) of 5-(2-bromophenyl)-1H-tetrazole: mp 178°-180 ° C.; NMR (DMSO-d6) δ7.50-7.64 (m, 2H), 7.67-7.74 (m, 1H), 7.83-7.91 (m, 1H). A 41.8 g (187 mmol) sample of this material was dissolved in 650 mL of methylene chloride and treated with 55.5 g (193 mmol) of triphenylmethyl chloride and 30 mL (220 mmol) of anhydrous triethylamine. The reaction was allowed to stir overnight at reflux, cooled to ambient temperature, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization from toluene/hexane gave 80.7 g (92%) of N-triphenylmethyl-5-(2-bromophenyl)-1H-tetrazole: mp 160°-162° C.; NMR (CDCl3) δ7.14-7.21 (m, 6H), 7.26-7.45 (m, 11H), 7.70 (dd, J=8 and 1.5 Hz, 1H), 7.89 (dd, J=7.5 and 2 Hz, 1H). A 34.05 g (73.0 mmol) sample of this material was dissolved in 1700 mL of THF under a nitrogen atmosphere and treated with 73 mmol of n-butyllithium in hexane. The reaction was allowed to stir for 17 min and then was treated with 24.9 mL (220 mmol) of trimethyl borate. The reaction was allowed to come to ambient temperature overnight while stirring, quenched with 10 mL of methanol, and concentrated in vacuo. The residue was dissolved in 1M NaOH and extracted with toluene to remove any unreacted starting material. The pH was adjusted to 6 with 6M HCl and the product extracted with toluene and dried (MgSO4). Hexane was added and the solution kept in the freezer overnight. Filtration provided 31.3 g (99%) of 2-(N-triphenylmethyl-tetrazol-5-yl)phenylboronic acid: NMR (CDCl3) δ7.13-7.21 (m, 7H), 7.33-7.42 (m, 8H), 7.49-7.55 (m, 2H), 8.15-8.19 (m, 1H), 8.21-8.26 (m, 1H).
Reaction SMILES: C([S:4][CH:5]([CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.S(=O)(=O)(O)O>C(O)C>[C:12]([CH2:11][CH:5]([SH:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)SC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C(S)CC(=O)c1ccccc1
Reaction time: 4 h
Yield: 68.1 %

Procedure:
To a solution of 2.80 g of ethyl 2-acetylthio-3-benzoylpropionate in 30 ml of ethanol was added 4 ml of 10N sulfuric acid, and the mixture was refluxed at heating with stirring for 4 hours. The ethanol was removed from the mixture by evaporation under redused pressure, and diethyl ether was added to the residue. The mixture was washed with water and dried over magnesium sulfate. The diethyl ether was removed from the mixture by evaporation, and the residue was purified by silica gel column chromatography using a mixture of hexane and diethyl ether as an eluent to give 1.62 g of ethyl 3-benzoyl-2-mercaptopropionate as an oil.
Reaction SMILES: [C:1]1([B-:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].O.S(O)(O)(=O)=O.[C:33]([P:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[C:20]1([B-:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[C:42]([PH+:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Temperature: 25 °C

Procedure:
A 300-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 16.4 g (48 mmol) of sodium tetraphenylborate and 66 ml of water were weighed in the flask, followed by stirring to dissolve sodium tetraphenylborate. While the stirring was continuously carried out, the aqueous solution of tri-tert-butylphosphine sulfate was added to the solution, and the mixture was stirred at 25° C. for 3 hours. After the completion of the reaction, the precipitated product was filtered off. The so obtained crystal was suspended in 100 ml of toluene at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of toluene. The crystal was then suspended in 100 ml of methanol at 50° C., and the suspension was cooled to 25° C. and filtered. The product filtered off was washed with 100 ml of methanol. The crystal obtained was dried to give 19.4 g of objective tri-tert-butylphosphonium tetraphenylborate as white crystal. The yield (mol %) was 93% based on tri-tert-butylphosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: CCCCCCc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 97 %

Procedure:
A suspension of 6 g of 5-(2-chlorophenyl)-7-[2-(4-n-hexylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 149°-151° C. and 5.2 g of Lawesson reagent in 100 ml of toluene is stirred at 40°-42° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 6 g of 5-(2-chlorophenyl)-7-[2-(4-n-hexylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 140°-145° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCC#N)ccc23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCc4nnn[nH]4)ccc23)CC1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 44.8 %

Procedure:
A mixture of 4-[7-(3-Cyano-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (24.5 mg, 62 μmol), as prepared in the preceding step, NaN3 (13.4 mg, 206 μmol), TEA.HCl (25.5 mg, 185 μmol), and toluene (100 μL) was tightly capped and stirred at 100° C. for 6.5 hr. The reaction was then allowed to cool to rt, partitioned with EtOAc (1 mL) and 0.1 M HCl (1 mL). The aqueous layer was then extracted with EtOAc (2×1 mL), the organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified via flash silica chromatography (3:2 EtOAc/acetone) to yield the title intermediate as an off-white solid (12.2 mg, 44%). LC/MS (ESI) calcd mass 439.2, found 440.1 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SCC1CC1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccnc2SCC2CC2)c(Cl)c1
Yield: 62.8 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (35 mg, 0.16 mmol) obtained in Step C of Preparation Example 18 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[C:12]([C@@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cc(OC3CCC(C(C)(C)C)CC3)ccc2s1

Procedure:
2-Methyl-benzothiazol-5-ol (2.5 g, 0.015 mol), cis-4-tert-butylcyclohexanol (2.84 g, 0.0182 mol), and Triphenylphosphine (4.76 g, 0.0182 mol) were combined in dry Toluene (100 mL, 1 mol) and stirred under nitrogen. Diisopropyl azodicarboxylate (3.6 mL, 0.018 mol) was added dropwise. The reaction was then stirred at RT overnight. Reaction was then concentrated to dryness and then residue was dissolved in DCM and 5 g of SiO2 was added. Solvent was removed under reduced pressure and resulting powder was loaded onto a 40 g column and purified via column chromatography using a gradient of 0-60% EtOAC/Hexanes.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:37][CH3:38])[CH:12]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>FC(F)(F)CO.CO>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:37][CH3:38])[CH:12]=2)[CH2:6]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 89 %

Procedure:
N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 79 mg, 0.46 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129 (which may be prepared by the method described for Intermediate 87), 150 mg, 0.38 mmol) and DIPEA (0.264 mL, 1.53 mmol) in 2,2,2-trifluoroethanol (3 mL). The mixture was heated at 140° C. in a microwave for 1 h. The mixture was then purified directly by ion exchange chromatography, using an SCX column (50 g) and eluting with 1:1 7M methanolic ammonia in CH2Cl2. Concentration of appropriate fractions in vacuo gave a brick red solid. This solid was suspended in CH3OH and the solid was collected by filtration, washed with CH3OH (10 mL) and dried in vacuo to give the title compound (160 mg, 89%) as a red solid; m/z: ES+ MH+ 474.61.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[NH:21]1[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([OH:26])=[O:25])[CH2:22]1.C([O-])([O-])=O.[K+].[K+].Cl>O.CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:21]2[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([OH:26])=[O:25])[CH2:22]2)[CH:3]=1
Reactant: O=C(O)C1CCCNC1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCCC(C(=O)O)C2)n1
Temperature: 140 °C
Reaction time: 5 h
Yield: 47.4 %

Procedure:
In a tube is combined (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [200 mg, 0.6 mmol, Intermediate (44)], nipecotic acid (194 mg, 1.5 mmol), K2CO3 (249 mg, 1.8 mmol) and 1-methyl-2-pyrrolidinone (2.5 mL). The tube is sealed and heated to 140° C. and stirred for 5 hours. The mixture is allowed to cool to ambient temperature, stand for 12 hours, diluted with water (20 mL) and acidified using 3M HCl. A precipitate forms and is collected by filtration and dried under high vacuum to afford 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-3-carboxylic acid [121 mg, 47%, Example 73] as a solid. LCMS RT=2.15 minutes, MS: 425 (M+H). IC50=0.8 nM
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=2)[NH:21][N:20]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24](/[CH:28]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)=[CH:25][CH:26]=2)[NH:21][N:20]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reactant: O=C1Cc2cccnc2N1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Yield: 28.2 %

Procedure:
The title compound (7 mg, 21%) was synthesized as yellow solid according to the method described for Example A67 using 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (9.3 mg, 0.07 mmol) and (E)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbaldehyde (17 mg, 0.068 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H, NH), 11.27 (s, 1H, NH), 8.62 (d, J=4.0 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H), 8.02-7.89 (m, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.63 (d, J=16.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.28 (t, J=6.0 Hz, 1H), 6.91 (dd, J=7.6 Hz, 5.6 Hz, 1H); MS ESI 366.1 [M+H]+, calcd for [C22H15N5O+H]+ 366.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A solution of [5-(3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine (III-80) (250 mg, 0.56 mmol), in dichloromethane (3 mL) at 0° C. was treated with TFA (2 mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane (3×5 mL) and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3 mL) and water (3 mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80° C. under vacuum to afford III-79 as an off-white powder (122 mg, 63%): mp 205–207° C.; 1H NMR (DMSO) δ 1.68–1.83 (2H, m), 2.65–2.80(4H, m), 6.80 (1H, s), 7.50–7.60 (4H, m), 7.80–7.90 (2H, m), 8.45–8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3(M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](Br)[N:9]=1)=[O:7].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:31]2[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=1[NH2:14])=[O:7]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NCC(O)(C(F)(F)F)C(F)(F)F
Product: Cc1ccc(-c2nc(C(=O)NCC(O)(C(F)(F)F)C(F)(F)F)c(N)cc2C(F)(F)F)cn1

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide (Ex. 1.28) and 2-methylpyridine-5-boronic acid analogously to Example 8. LC-MS Rt 1.28 min; 477[M+H]+; (Method 2minLC_v002); 1H NMR (400 MHz, MeOD) δ 8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s), 2.62 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([O:22][CH2:23][CH:24]=[CH2:25])[CH:19]1[O:21][CH2:20]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:23]([O:22][CH2:18][CH:19]([OH:21])[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:20][CH:19]([OH:21])[CH2:18][O:22][CH2:23][CH:24]=[CH2:25])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH:24]=[CH2:25]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: C=CCOCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COCC=C)cc2)cc1
Temperature: 110 °C

Procedure:
Bisphenol A (228 g; 1 mole), allyl glycidyl ether having an epoxide content of 8.64 equiv./kg (231.5 g; 2 equiv.), and benzyltrimethylammonium chloride (2 g) were stirred together and heated to 110° C., at which temperature an exothermic reaction commenced, the temperature rising spontaneously to 120° C. When the temperature began to fall, heating was resumed to keep the mixture at 120° C. After 11/2 hours at this temperature the mixture was heated at 150° C. for 3 hours. The residual mixture had an epoxide content of 0.20 equiv./kg, indicating that the reaction was essentially complete.