Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:26]1[C:27]([CH3:43])=[C:28]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=[CH:30][CH:31]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:17][CH2:16][CH:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:35]([O:34][C:33]([NH:32][C:28]1[C:27]([CH3:43])=[C:26]([CH:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:14]5)=[CH:10][CH:11]=4)[NH:6][C:5]=3[CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[NH:1][CH2:2]2)[CH:31]=[CH:30][CH:29]=1)=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C1NCC(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 3-(2-amino-1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.1010 g, 0.169 mmol) in 1,4-dioxane (4.82 mL) was added 50% ethyl 2-oxoacetate/toluene (0.067 mL, 0.337 mmol) at 10° C. The cold bath was removed, and the reaction was stirred to room temperature for 3 h. The reaction was concentrated in vacuo to give crude ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate which was used in the subsequent step. This was added to p-xylene (41.6 mL) and 10% Pd/C (0.310 g, 0.291 mmol). The reaction was heated to 125° C. for 4.5 hr and cooled to room temperature. The solution was filtered through a pad of CELITE® and rinsed with EtOAc (150 mL). The filtrate was washed with water (40 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 0-30% EtOAc/CH2Cl2. Appropriate fractions (20% elution) were combined, concentrated in vacuo to give the desired product (0.1487 g, 0.219 mmol, 15.0% yield) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][CH:8]([F:10])[C:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)c1cccc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 1-bromo-3-(difluoromethyl)benzene (0.72 g, 3.48 mmol), tributyl(1-ethoxyvinyl)tin (1.38 g, 3.83 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.24 g, 0.35 mmol) in toluene (12 mL) is heated at 100° C. under nitrogen atmosphere for 16 hours. After cooling to room temperature, 2M hydrochloric acid (12 mL) is added to the mixture. Then the resulting mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica-gel eluting with n-hexane/ethyl acetate (30:1) to give 0.58 g (98% yield) of the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>C(O)(=O)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([N:1]4[CH:20]=[CH:24][CH:23]=[CH:22]4)[C:3]=3[F:17])[N:6]=2)[CH2:10][CH2:11]1
Reactant: Cc1c(N)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1c(-n2cccc2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
6-Amino-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-319) (29 mg, 0.13 mmol) was dissolved in acetic acid (2 ml), then at room temperature, 2,5-dimethoxytetrahydrofuran (49 μl, 0.38 mml) was added. The solution was stirred at 100° C. for 3 hours, then cooled to room temperature. The solvent was evaporated away under reduced pressure, the resulting residue was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=9:1, v/v) to obtain the entitled compound (28.5 mg, 81%) as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[CH:47]1(S(Cl)(=O)=O)C[CH2:48]1>>[CH:46]1([S:43]([NH:42][CH2:41][CH2:40][NH:39][C@:5]23[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)(=[O:45])=[O:44])[CH2:48][CH2:47]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)C3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using cyclopropanesulfonyl chloride as the reagent in Step 1. The product was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 677.52 (M+H)+, 2.32 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.55 (br. s., 1H), 7.98 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.76 (br. s., 1H), 5.99 (br. s., 1H), 5.21 (d, J=5.0 Hz, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.92-3.71 (m, 1H), 3.69-3.55 (m, 1H), 3.23 (br. s., 2H), 2.91-2.70 (m, 1H), 2.63-2.44 (m, 1H), 2.25-1.02 (m, 26H), 1.70 (s, 3H), 1.18 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[OH:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]12(C3C=C(C=CC=3O)C=O)CC3CC(CC(C3)[CH2:23]1)[CH2:29]2>>[C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH:22]([CH3:29])[CH3:23])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OC(C)C)c1
Yield: 75.4 %

Procedure:
When methyl 4-(1-admantyl)-3-hydroxybenzoate was substituted for 3-(1-admantyl)-4-hydroxybenzaldehyde in Example 60, Step A, the identical process afforded the title compound (0.95 g, 75.4%) as a colourless solid. 1H-NMR (CDCl3) 1.39 (d, 6H, J=6 Hz); 1.75 (5, 6H); 2.05 (s, 3H); 2.11 (s, 6H); 3.87 (s, 3H); 4.69-4.71 (m, 1H); 7.24 (d, 1H, J=8.1 Hz); 7.47 (b, 1H); 7.51 (dd, 1H, J=1.55, 8.09 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH:31](Cl)(Cl)Cl>[OH-].[Na+].C(OCC)C>[CH3:31][N:16]1[CH2:17][CH2:18][O:19][CH:14]([CH:6]([O:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: ClC(Cl)Cl
Reactant: COc1ccccc1OC(c1ccc(Cl)cc1)C1CNCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1OC(c1ccc(Cl)cc1)C1CN(C)CCO1
Temperature: 0 °C
Yield: 82 %

Procedure:
To a solution of 2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine (7.35 g) in CHCl3 (50 ml), 2 N NaOH (18.2 ml) was added; the mixture was cooled to 0° C. and ethyl chloroformiate (3.5 ml) was dropped over 30 minutes. Stirring and cooling at 0° C. was maintained for 1 hour; the organic phase was separated, washed with water and dried over anhydrous CaCl2. The evaporation to dryness of the solvent gave a colourless oil which was dissolved in diethyl ether (100 ml) and added, at room temperature, to a suspension of LiAlH4 (2.5 g) in anhydrous diethyl ether (200 ml). The mixture was stirred at room temperature for 20 hours; water (2.5 ml), 15% NaOH (2.5 ml) and water (7.5 ml) were added. After filtration, the ethereal layer was separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and dried over anhydrous Na2SO4. After evaporation to dryness of the solvent, 4-methyl-2-[α-(2-methoxy-phenoxy)-4-chloro-benzyl]-morpholine was obtained as oil (6.25 g; yield 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][N:8]([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1I
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1nn(CCOC2CCCCO2)cc1I
Yield: 39 %

Procedure:
A suspension of Intermediate 74b (2.72 g, 10.2 mmol) in acetonitrile (27 mL) was treated with caesium carbonate (5.0 g, 15.3 mmol) then 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.70 mL, 11.2 mmol) and the mixture was stirred at 60° C. for 3.5 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, isolating the lower running spot to give the title compound as a colourless glass (1.57 g, 39%). LCMS (Method 3): Rt 3.67 min, m/z 417 [M+Na+].
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Br)nc1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 4.85 g of 6-bromo-pyridine-3-carboxaldehyde in 50 mL of MeOH at 0° C. was added 1.93 g of NaBH4. This mixture was allowed to warm to room temperature. Upon completion of the reaction, the reaction mixture was concentrated to a residue, which was partitioned between ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. Purification by flash chromatography (silica, heptanes/ethyl acetate) provided 4.83 g of (6-bromo-pyridin-3-yl)-methanol.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCCCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.67 h
Yield: 109.2 %

Procedure:
To a tetrahydrofuran (300 ml) solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (26.58 g), 1.58 M of n-butyl lithium (tetrahydrofuran solution; 100 ml) was added under argon atmosphere at −78° C., and the mixture was stirred at the same temperature for 40 minutes. To the mixture, a tetrahydrofuran (100 ml) solution of 5-phenylpentanoyl chloride (32.4 g) was added, followed by stirring at −78° C. for 5 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, dried over anhydrous sodium sulfate and concentrated to give the title compound (55.29 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][C:24]1[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:8](=[O:19])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Cl
Reactant: N#Cc1ccccc1CBr
Product: Cn1c(=O)n(Cc2ccccc2C#N)c(=O)c2c1nc(Br)n2Cc1ccccc1Cl

Procedure:
8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (75A) and alpha-bromo-o-tolunitril were reacted and purified as described in the General procedure G, Step B, to afford 75B as white crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][C:38]([O:40][CH3:41])=[O:39])[CH:12]=[CH:13][C:14]=1[C@H:15]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[N:16]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)C1C=CC=CC=1>CCOC(C)=O.CO>[OH:8][C:9]1[CH:10]=[C:11]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:12]=[CH:13][C:14]=1[C@H:15]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[N:16]1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1
Reactant: COC(=O)C=Cc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(F)cc2)c(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(F)cc2)c(O)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Dissolve the product of Example 5 (0.266 g, 0.48 mmol) in EtOAc (16 mL), dilute with CH3OH (20 mL) and purge with N2. Add 20% Pd/C (0.05 g), purge the mixture with H2 and then stir under a balloon of H2 overnight. Filter the reaction mixture through celite. Wash the filter cake with EtOAc and concentrate the filtrate to give 0.156 g of the title compound as a colorless oil. HRMS calc'd for C28H28 NO4 :M+H 462.2081; found 462.2070.MS (CI): 462 (M+1,37), 351 (17), 293(41 ), 138(100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])=[CH:20][C:19]=1[C:30]([F:33])([F:32])[F:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])=[CH:20][C:19]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.030 g, 0.11 mmol), 2-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-propanoic acid (0.030 g, 0.11 mmol) and NEt3 (0.070 mL, 0.50 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water, and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.005 g, 10%). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.30-7.51 (m, 4H), 7.14 (dd, J=8.8, 8.4 Hz, 2H), 3.22 (m, 2H), 2.69 (t, J=6.4 Hz, 2H), 1.64 (s, 6H); 1.62 (m, 2H); MS: (ES) m/z calculated for C23H20ClF4N3O [M+H]+ 466.1, found 466.1.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:19]([C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.CO>CN(C=O)C>[NH:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:19]([C:29]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
H-Glu(OBzl)-OH (39.4 g, 166 mmol) was stirred with Boc-Ser(Bzl)-OSu (65.0 g, 166 mmol) in 900 ml DMF overnight in the presence of Et3N (2.3 ml, 165 mmol). More Et3N was added during this time in order to maintain the reaction slightly basic. The clear solution was evaporated to dryness and the oily residue partitioned between EtOAc (1.5 liters) and 5% HOAc (2 liters). The organic layer was washed with H2O (2 times), dried over Na2SO4, and concentrated to a clear oil (90.0 g) which was taken up in 3 liters of ether and treated with 25 ml of cyclohexylamine The solid formed was recrystallized from MeOH and ether: yield, 76.2 g (74.8%); mp 154°-156.5°; [α]D25 =+6.32° (c l, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[O:21])[CH:15]=[CH:14][N:13]=[CH:12]1>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:23][CH:24]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)NCCCn2ccnc2)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(Nc2ccc(C(=O)NCCCn3ccnc3)cc2)nc1N
Yield: 2.1 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (200 mg, 1.3 mmol) and 4-[N-(3-imidazol-1-ylpropyl)carbamoyl]aniline (Method 3; 633 mg, 2.6 mmol) in NMP (10 ml) was heated at 120° C. for 48 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried and the solvent removed by evaporation, the residue was triturated with ether/hexane and the product collected by filtration to give the title compound (10 mg, 2%). NMR: 1.92 (q, 2H) 3.20 (q, 2H), 4.00 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.55 (s, 2H), 7.62 (s, 1H), 7.86 (d, 2H), 8.32 (t, 1H), 8.38 (s,1H), 9.90 (s, 1H); m/z 363 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)c1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccc(F)cn2)n1
Temperature: 90 °C
Reaction time: 7 h
Yield: 69.1 %

Procedure:
To a solution of ethyl-1H-pyrazole-3-carboxylate (25.0 g, 178.4 mmol) and 2-bromo-5-fluoropyridine (47.1 g, 267.6 mmol) in DMF (300 mL), copper(I) iodide (8.5 g, 44.6 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (28.1 mL, 178.4 mmol) and Cs2CO3 (116.2 g, 356.8 mmol) were added, and the resulting mixture was stirred for 7 hours at 90° C. The reaction mixture was allowed to cool to room temperature, then water and EtOAc were added thereto, followed by filtration through Celite®. The organic layer was taken out from the filtrate, washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane/EtOAc=70/30 to 0/100). The obtained solid was stirred and washed in hexane/EtOAc=4/1 and filtered out to obtain the title compound (29.0 g) (colorless solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:6]3/[C:7](=[O:14])[NH:8][C:9]4[C:5]/3=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: COc1cc2c(cc1OC)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Yield: 66.9 %

Procedure:
The title compound (43 mg, 67%) was synthesized as an orange yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5,6-dimethoxyindolin-2-one (38.6 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.36 (s, 1H), 8.14 (s, 1H), 7.95-7.85 (m, 2H), 7.57 (s, 1H), 7.46-7.37 (m, 1H), 7.24 (s, 1H), 6.52 (s, 1H), 3.78 (s, 3H), 3.53 (s, 3H); MS ESI 322.1 [M+H]+, calcd for [C18H15N3O3+H]+ 322.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9].C1(C)C=CC=CC=1.S(O[CH2:37][CH2:38][Cl:39])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[Cl:39][CH2:38][CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(c1ccccc1OCCCl)c1cccc2[nH]ccc12

Procedure:
6 g of the product of Step D of Example 3, 192 ml of toluene, 90 ml of acetonitrile, 2.16 g of tetrabutyl ammonium hydrogen sulfate, 9.18 ml of 2-chloroethanol tosylate and 90 ml of 5N sodium hydroxide were stirred for 72 hours at 50° C. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica (eluant:methylene chloride) to obtain 5.39 g of the desired product which was used as is for the following step.