Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:59])[N:24](CC5C=CC(OC)=CC=5)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:42][S:43]([C:46]6([CH3:49])[CH2:48][CH2:47]6)(=[O:45])=[O:44])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:62])[C:13]([O:60][CH3:61])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:59])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:42][S:43]([C:46]6([CH3:49])[CH2:48][CH2:47]6)(=[O:45])=[O:44])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:62])[C:13]([O:60][CH3:61])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCNC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To compound 139 (106 mg, 0.120 mmol) dissolved in dichloromethane (18 mL) were added triethylsilane (38 μL, 0.240 mmol) and TFA (9 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated and co-evaporated trice with toluene. The residue was dissolved in dichloromethane and the organic phase was washed twice with saturated NaHCO3 solution. The organic phase was dried, filtered, and concentrated and the crude product was purified by flash column chromatography (toluene/ethyl acetate 1:1) to yield the title compound (73 mg, 80%) as a slightly yellow solid. LC-MS purity: >95%. (M+H)+ cald: 765.3. found: 765.7.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCCCC2)nc1

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and piperidine. MS calcd. for C27H25ClN4O2 [(M+H)+] 473.2, obsd. 473.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl.O>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 10 mL round-bottomed flask was added tert-butyl 4-(4-aminophenylthio)piperidine-1-carboxylate (100 mg, 0.324 mmol) and triethylamine (249 μl, 1.783 mmol) in dichloromethane (3242 μl). The mixture was cooled to −78° C. and acetyl chloride (115 μl, 1.621 mmol) was added. The solution was warmed to room temperature, stirred for 1 h and then diluted with water and additional dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organics were dried with sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@@H:24]([C:37]1[N:41]2[C:42]3[S:56][C:55]([CH2:57][CH3:58])=[CH:54][C:43]=3[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:45][CH2:46][C:40]2=[N:39][N:38]=1)[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[CH3:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[N:67]=[C:68]=[O:69].C(N(CC)CC)C.O>CN(C=O)C>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[C:43]2[CH:54]=[C:55]([CH2:57][CH3:58])[S:56][C:42]=2[N:41]2[C:37]([C@H:24]([NH:23][C:68]([NH:67][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[O:60][CH3:59])=[O:69])[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[N:38][N:39]=[C:40]2[CH2:46][N:45]=1
Reactant: CCc1cc2c(s1)-n1c(nnc1[C@H](N)CCC(=O)OCc1ccccc1)CN=C2c1ccccc1Cl
Reactant: COc1ccccc1N=C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(s1)-n1c(nnc1[C@@H](CCC(=O)OCc1ccccc1)NC(=O)Nc1ccccc1OC)CN=C2c1ccccc1Cl

Procedure:
Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)butanoate di-p-toluenesulfonate (2.0 g) and 2-methoxyphenyl isocyanate (0.34 ml) were dissolved in DMF (20 ml). Triethylamine (0.97 ml) was added and the mixture was stirred. Water was added to the reaction mixture. The mixture was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 1.19 g of benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)-4-(3-(2-methoxyphenyl)ureido)butanoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[C:33](=[O:36])([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.C[C:45]([CH3:47])=[O:46]>>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:11][CH2:12][O:16][CH2:17][CH2:18][O:46][CH2:45][CH2:47][O:36][CH3:33])[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: CC(C)=O
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)[O-]
Agent: [K+]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOCCOCCOC)c1
Temperature: 25 °C

Procedure:
To a solution of 100 mg (0.236 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in acetone (5 ml) is added potassium carbonate (326 mg, 2.36 mmol) followed by the mesylate prepared in Step A (5 ml, 1.18 mmol). The reaction mixture is heated at reflux for 2 days. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by flash chromatography on silica gel using dichloromethane/t-butyl methyl ether (1:1) to provide the title compound as a yellow oil. Yield: 101 mg (75%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:13])([CH3:12])[CH:9]=[CH:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:11][CH:10]=[CH:9][C:8]([CH3:13])([CH3:12])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC=CC(C)(C)C(C)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)C(C)(C)C=CCBr
Yield: 86.6 %

Procedure:
A mixture of 920 mg (5 mmoles) of ethyl 2,3,3-trimethyl-4-hexenoate, 10 ml of carbon tetrachloride, 107 mg (6 mmoles) of N-bromosuccinimide, and 50 mg of benzoyl peroxide was heated under reflux for about two hours. The insoluble succinimide was removed by filtration. The filtrate was washed successively with saturated aqueous sodium bicarbonate solution and water, then dried over magnesium sulfate. The dried solution was distilled to give 1.14 g (86% yield) of ethyl 6-bromo-2,3,3-trimethyl-4-hexenoate, b.p. 80°-81°/0.8 mm.
Reaction SMILES: [H-].[Na+].C(OC(=O)CC[SH:9])C.[CH2:11]([O:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OC1C=CC=C(CC2C=CC(N3CC(=O)NS3(=O)=O)=C(O)C=2)C=1C#N>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([SH:9])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: CCOC(=O)CCS
Agent: N#Cc1c(O)cccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of NaH (60%, 1.21 g, 30.3 mmol) in dry DMF (20 mL) under N2 at 0° C. is added dropwise 3-mercaptopropionic acid ethyl ester (1.9 mL, 15.2 mmol) and 2-benzyloxy-4-fluoro-1-nitrobenzene (intermediate from Example 27) (2.5 g, 10.1 mmol) in dry DMF (10 mL). The reaction is allowed to warm to ambient temperature and stirred for 4 days. The mixture is then diluted with EtOAc (100 mL) and extracted with 1N HCl (50 mL). The organics are washed with brine and dried with Na2SO4. Evaporation yields a yellow oil which is purified by flash chromatography (30-50% EtOAc). The title compound is isolated as a yellow oil: MS (M−H)−=260.2.
Reaction SMILES: [CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[C:12]1([CH3:23])[CH:17]=[CH:16][C:15]([S:18]([O:21]C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:12]1([CH3:23])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N+:6]=1[CH3:12]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc2[se]c(C)nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1ccc2[se]c(C)[n+](C)c2c1
Yield: 183.1 %

Procedure:
Into a sealed tube were placed 4.20 g (20.0 mmoles) of 2,5-dimethylbenzoselenazole, 3.90 g (21.0 mmoles) of methyl paratoluenesulfonate and 20 ml of chloroform. A reaction and treatment were conducted by the same procedure as in Reference Example 4, giving 7.62 g (yield: 96%) of 2,3,5-trimethylbenzoselenazolium paratoluenesulfonate as a pink powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([OH:21])=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1.C([O-])(=O)C.[Na+]>O>[C:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([OH:21])=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)(=[O:3])[CH3:2]
Reactant: NC1CCCc2c(ccc(O)c2O)C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1CCCc2c(ccc(O)c2O)C1
Reaction time: 4 h

Procedure:
Acetic anhydride is added to a mixture of 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol Cannon, J. G., et al., J. Med. Chem., 27, 922(1984)! in water containing sodium acetate. The mixture is chilled and stirred in ice for 4 hours followed by filtration to give N-acetyl-6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol. Benzyl bromide, powdered potassium carbonate and acetone is added to the isolated N-acetyl-6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol and the mixture is stirred for 18 hours. The reaction mixture is poured into water, extracted and concentrated in vacuo to give N-acetyl-6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene. Hydrolysis with ethanolic sodium hydroxide gives 6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OC(C1NC(C(O)=O)=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH:16]([C:13]1[N:12]([CH3:18])[C:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=C(O)c1ccc(C(=O)OCc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C=O)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (from the preparation of Intermediate 18) (400 mg, 1.75 mmol) in DMF (10 mL) is added cesium carbonate (853 mg, 2.62 mmol) and MeI (297 mg, 2.09 mmol). The mixture is stirred at room temperature for 2 hours then water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give benzyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate; HPLC Retention time 1.26 minutes (condition C): MS 244.3 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH3:10])[C:7]([C:11]([OH:13])=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.CN[C:16]1[N:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[N:22]1C=CC=C[CH:23]=1.ClCCl.CO>ClCCl>[N:17]1[CH:16]=[CH:21][C:20]([N:22]([CH3:23])[C:11]([C:7]2[C:8]([CH3:10])=[N:9][C:4]([CH:1]3[CH2:2][CH2:3]3)=[N:5][CH:6]=2)=[O:13])=[CH:19][N:18]=1
Reactant: c1ccncc1
Reactant: CNc1cccnn1
Reactant: Cc1nc(C2CC2)ncc1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(C2CC2)ncc1C(=O)N(C)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
2-Cyclopropyl-4-methyl-pyrimidine-5-carboxylic acid (200 mg, 1.12 mmol) was dissolved in anhydrous dichloromethane (20 ml). 4-N,N-Dimethylaminopyridine (23 mg, 0.2 mmol) and N,N-diisopropyl carbodiimide (0.17 ml, 1.12 mmol) were sequentially added and the reaction mixture was stirred at room temperature for 2 hours. Ak methylaminopyridazine (147 mg, 1.35 mmol) was dissolved in anhydrous dichloromethane (5 ml) and together with pyridine (0.35 ml, 1.12 mmol) added to the reaction mixture. Stirring at room temperature was continued for 15 hours. The progress of the reaction was monitored by thin layer chromatography (dichloromethane/methanol 9:1). The reaction mixture was diluted with dichloromethane (50 ml), washed two times with distilled water (5 ml each). The organic phase was dried over sodium sulfate and the organic solvent was evaporated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol, gradient: 100/0 to 90/10 (v/v), duration: 50 min). The title compound was isolated as a brownish oil (119 mg, yield: 39%, purity: 95%).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O.[NH2:25][NH2:26]>CCO>[NH2:2][C:1]1[NH:26][N:25]=[C:7]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([S:13]([CH3:12])(=[O:14])=[O:15])=[CH:17][CH:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CNc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Methylsulphonylbenzylamine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(methylsulfonyl)benzyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:7]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 60 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (150 mg, 0.22 mmol), copper (I) iodide (83 mg, 0.44 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (600 mg, 4.4 mmol) to a solution of 1-fluoro-4-iodo-2-nitrobenzene, (prepared as described in PREPARATION 46), (1.22 g, 4.6 mmol) in triethylamine (6.6 mL, 65.3 mmol). Stir at 60° C. for 18 h then concentrate. Purify by silica gel chromatography, eluting with a gradient of 100:0 to 90:10 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 95:5 to 60:40 hexanes:ethyl acetate, to give the title compound as a light yellow solid (650 mg, 54%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([P:16](Cl)(Cl)=[O:17])([CH3:15])[CH3:14]>>[CH:13]([P:16]1(=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)P1(=O)c2ccccc2CN1C(C)(C)C
Yield: 39 %

Procedure:
The procedure of Example 30 was employed utilizing N-t-butyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -70° C. The crude product produced as a result of the chromatographic separation was distilled at 130° C. and 0.1 mm to yield a colorless oil. The colorless oil was slurried in petroleum ether to yield 1-isopropyl-2-t-butyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.8 g, 39% yield) having a melting point of 67°-70° C. and the following analysis:
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:40])[NH:30][C:31]3[NH:32][N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=3)[CH:24]=[CH:23]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:19][C:14]4[C:15]5[CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:28][CH:27]=3)[CH:23]=[CH:24]2)=[O:40])[NH:32][N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1

Procedure:
A solution of 4-[1-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (300 mg, 0.55 mmol), DCM (5 mL), and TFA (5 mL) is stirred at it for 2 h. At that point the solution is concentrated and the residue separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 446.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.37 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.88 (d, J=3.5 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.08 (dd, J=9.1, 2.3 Hz, 1H), 6.71 (d, J=3.8 Hz, 1H), 6.38 (br. S., 1H), 6.06 (br. S., 1H), 4.00 (d, J=6.1 Hz, 2H), 3.05-3.15 (m, 1H), 3.00 (dd, J=17.2, 3.5 Hz, 1H), 2.47 (dd, J=17.2, 10.4 Hz, 1H), 1.36 (s, 9H), 1.34 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:43]([CH:50]1[CH2:55][CH2:54][CH2:53][N:52]([C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)[CH:9]=2)=[O:13])[CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: c1ccc(CC2CCCNC2)cc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (100 mg, 0.4 mmol) was dissolved in dry DMF (3 mL) and HATU (183 mg, 0.48 mmol) was added followed by 3-benzylpiperidine (75 mg, 0.42 mmol) and NMM (0.13 mL, 1.2 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was then diluted with EtOAc and the organic layer was washed with water, 1.5N HCl solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get (3-benzylpiperidin-1-yl)(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanone (70 mg, yield 44%): 1H NMR (400 MHz, CDCl3) δ 8.15-8.01 (m, 2H), 7.59-7.47 (m, 2H), 7.32-7.21 (m, 2H), 7.06-6.97 (m, 3H), 4.63 (m, 1H), 3.59-3.56 (m, 1H), 2.83-2.51 (m, 4H), 1.93-1.84 (m, 3H), 1.26-1.22 (m, 2H). MS (ESI) m/z: Calculated for C22H20F3N3O2: 415.41. found: 416.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[OH:19].[H][H].Br[CH:23]([CH2:31][CH3:32])[C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C1([O-])C=CC=CC=1.[Na+]>C1(C)C=CC=CC=1.O.CS(C)=O>[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH2:32][CH2:31][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CCC(Br)C(C)(C)C(=O)OC
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)c(C)cc1O
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)cc1C
Temperature: 75 °C

Procedure:
A 1 liter, 3 neck round bottom flask fitted with an overhead stirrer is charged with 100 mL of dimethylsulfoxide and 6.0 g of 60% sodium hydride, washed free of mineral oil with toluene (3.6 g contained; 150 mmol), then a solution of 34.2 g 150 mmol) of 2,5-dimethyl-4-(phenylmethoxy)-phenol (Example K) in 200 mL of toluene is added at 20°-25° C. When hydrogen evolution is complete, 40.1 g (1.2×150 mmol) of 5 bromo-2,2 dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) is added and the temperature is raised to 75° C. When the temperature reaches 55° C., a solid separates (sodium phenolate). After 18 hours overnight the mixture is heated to reflux for 4 hours; then the mixture is cooled and 200 mL of water is added. The aqueous layer is extracted with diethyl ether and the organic layers are combined and the solution is washed with water, dried (magnesium sulfate) and evaporated leaving 65.7 g of a dark brown oil which crystallizes on standing. Recrystallization from hexane in the presence of charcoal affords 39.5 g of the title compound; mp 75.5°-76.5° C.