Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:12])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:16].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH3:12][C:3]1([C:2]([OH:16])=[O:1])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(CO)Cc2ccccc2O1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1(C(=O)O)Cc2ccccc2O1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
The 2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran (16.4 g) and potassium hydroxide (5.2 g) in water (150 ml) were mixed and cooled to 5°. Potassium permanganate (20 g) was added portionwise over 45 minutes to the stirred mixture maintained below 12°. After the addition was complete stirring was continued for 1 hour and the mixture was then diluted with water. Sodium metabisulphite was added to destroy the precipitated MnO2 followed by an excess of sodium carbonate. The basic aqueous phase was washed with methylene chloride and then acidified with 2 N hydrochloric acid. Extraction with methylene chloride followed by washing, drying and evaporation of the extracts gave the carboxylic acid (3.0 g); I.R. νmax 1720 cm-1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1.CC1C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1>C(OCC)C.CS(C)=O>[C:12]([C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[CH:30][NH:31][CH:32]=1)(=[O:13])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1c[nH]cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
A suspension of NaH (80% in paraffin) (3.97 g; 0.165 moles) in anhydrous ethyl ether (100 ml), maintained under nitrogen stream, is dropwise added with a solution of 3-(4-chlorophenyl)-1-phenyl-2-propen-1-one (18.11 g; 0075 moles) and tosylmethylisocianide (TOSMIC) (14.60 g; 0.075 moles) in anhydrous dimethylsulfoxide (170 ml) diluted with anhydrous ethyl ether (300 ml). Upon the additions are completed, the mixture is maintained under stirring at room temperature for 3 hours. After dilution with water (800 ml) the precipitate is filtered, washed with absolute ethanol and lastly with petroleum ether. There are obtained 10.40 g (yield 49.4%) of 4-benzoyl-3-(4-chlorophenyl)-1H-pyrrole, which is crystallized from N,N-dimethylformamide and water (m.p.: 232°-235° C.).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH:14]=[CH:13]1.FC(F)(F)C(O)=O>[OH-].[Na+]>[CH3:8][O:9][C:10](=[O:41])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)Cn1ccc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCc2ccc(S(=O)(=O)N3CCN(c4ccc(OC(F)(F)F)cc4)CC3)cc21

Procedure:
Triethylsilane (0.13 mL, 0.77 mmol) was added to a solution of {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (82 mg, 0.16 mmol) and trifluoroacetic acid (4 mL) at rt. After 1 H, more triethylsilane (0.2 mL, 1.2 mmol) was added. After an additional 4 H, the reaction was poured into 1.2 M NaOH (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried, filtered, concentrated and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid methyl ester: MS (ESI): 500.1 (M+H). {6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid methyl ester was hydrolyzed following the procedure outlined in Example 1 Step 2 to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-acetic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.24 (d, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 6.93 (d, 1H), 6.68 (s, 1H), 4.05 (s, 2H), 3.57 (t, 2H), 3.24-3.17 (m, 4H), 3.03 (t, 2H), 3.00-2.94 (m, 4H); MS (ESI): 486.1 (M+H).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]2=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[OH:17][CH2:3][C:2]1([CH3:1])[CH2:12][CH:11]1[C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:4]
Reactant: COCOc1cccc2c1C1CC1(C)C(=O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1cccc(O)c1C1CC1(C)CO
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
To a solution of 1a-methyl-7-{[(methyloxy)methyl]oxy}-1a,7b-dihydrocyclopropa[c]chromen-2(1H)-one (Intermediate 122, 360 mg) in dry tetrahydrofuran (15 ml) stirred under nitrogen at 0° C. was added a solution of lithium aluminium hydride (1.0M in THF, 1.537 ml, 1.537 mmol) and the reaction mixture was stirred at that temperature for 20 minutes. The reaction was then diluted with THF (20 ml) and quenched with the addition of Na2SO4.10H2O (10 eq) leaving the mixture under stirring for 30 minutes. The reaction was diluted with ethyl acetate, dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from cyclohexane/ethyl acetate 5/1 to cyclohexane/ethyl acetate 1/1) to give the title compound as a white solid (307 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]2=[N:15][CH:16]=[C:17]([C:20]([O:22]CC)=[O:21])[C:18](=[O:19])[N:4]2[CH:3]=1>C(O)(=O)C.Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]2=[N:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2c3cc([N+](=O)[O-])ccc3c(C)cn2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cn2c(=O)c(C(=O)O)cnc2c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Yield: 75.7 %

Procedure:
A suspension of ethyl 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (260 mg) in a mixture of acetic acid (6 ml) and 36% hydrochloric acid (3 ml) was refluxed for 50 minutes. The mixture was cooled to 0° C. to give yellow solid. The yellow solid was collected and dried to give 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (180 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]2[N:11]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:12]=[CH:13][C:5]=12
Reactant: Clc1cnc2[nH]ccc2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 60% sodium hydride in mineral oil (1.390 g, 34.8 mmol) in N,N-dimethylformamide (60 mL) at 0° C. was added a solution of 4,5-dichloro-1H-pyrrolo[2,3-b]pyridine (Adesis, 5.0 g, 26.7 mmol) in N,N-dimethylformamide (20 mL) slowly over 5 minutes. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was cooled to 0° C. and a solution of p-toluenesulfonyl chloride (5.35 g, 28.1 mmol) in N,N-dimethylformamide (20 mL) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours. Additional p-toluenesulfonyl chloride (500 mg, 2.62 mmol) was added, and the mixture was stirred another 1 hour at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 40-70% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 341.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl:27][C:28]1[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:31]5[N:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Clc1ccc(Cl)nn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(Cl)nn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,6-dichloro-pyridazine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=471/473 (Cl) [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>[I-].[Na+]>[C:1]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCCCCCP(=O)(OCC)OCC)cc1

Procedure:
[I; Ar is 4-C2H5OOCC6H4, Y is O(CH2)6, R is C2H5 ] was prepared from 15 g of 6-(4-carbethoxyphenoxy)hexyl bromide, 8.3 g of triethyl phosphite and a crystal of sodium iodide as a catalyst, according to the procedure of Example 1, and had the b.p. 190°-196° C. (0.2 mm); yield 9.5 g; MIC vs. herpes simplex type 2=6 mcg/ml. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)=[C:9]([N+:26]([O-:28])=[O:27])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]>C(OCC)(=O)C.C1CCCCC1>[CH:29]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[C:9]([N+:26]([O-:28])=[O:27])[CH:8]=1)=[O:6])([CH3:31])[CH3:30]
Reactant: COC(=O)c1ccc(-c2c([N+](=O)[O-])cc(C(=O)N(C(C)C)C(C)C)cc2[N+](=O)[O-])cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)c1cc([N+](=O)[O-])c(-c2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1)C(C)C
Yield: 103.4 %

Procedure:
Using the procedure of Example 19, Stage C, 244.4 mg of product B prepared in Example 19, Stage B were reacted to obtain 244.5 mg of the expected product with a Rf=0.146 (cyclohexane/ethyl acetate 1/1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[CH:37]=[C:38]2[N:44]=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1>>[N:44]1[C:38]2[C:39](=[N:40][CH:41]=[C:36]([C:18]3[CH:17]=[C:16]4[C:21]([CH2:22][CH:23]([CH3:24])[N:14]([C:12]5[CH:13]=[C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[N:9]=[C:10]([NH2:34])[N:11]=5)[CH2:15]4)=[CH:20][CH:19]=3)[CH:37]=2)[NH:42][CH:43]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3cnc4[nH]cnc4c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 116 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (Example 116, Step 1) and 6-bromo-3H-imidazo[4,5-b]pyridine (Focus synthesis, Cat. No. FS000626). LCMS (M+H)+: m/z=456.2.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[N:4]([CH3:13])[N:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([NH:1][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])=[N:3]1
Reactant: CCOC(=O)c1c(N)nn(C)c1C
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])nn(C)c1C
Temperature: 0 °C

Procedure:
Ethyl 3-amino-1,5-dimethylpyrazole-4-carboxylate (5.5 g), 2,5-difluoronitrobenzene (6.6 g) and anhydrous potassium carbonate (8.9 g), were stirred in dimethylsulphoxide (60 ml) under dry nitrogen at 70° C. for 20 hours. The mixture was poured on to 300 ml of ice-cold dilute hydrochloric acid, extracted with chloroform (3×), washed with water (2×), dried with magnesium sulphate and the solvent evaporated under reduced pressure. The yellow-brown residue was crystallized from ethanol to give the title compound having a m.p. of 174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=1.[F:17][C:18]([F:28])([F:27])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CCOC(C)=O.O.CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]([F:28])([F:17])[F:27])[CH2:21][CH2:22]2)=[O:14])=[CH:10][N:9]=1
Reactant: O=C(O)c1ccc(-c2ccccc2F)nc1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial was added 6-(2-fluorophenyl)nicotinic acid (100 mg, 0.46 mmol), 1-(2,2,2-trifluoroethyl)piperidin-4-amine (83.8 mg, 0.46 mmol), EDAC (97.1 mg, 0.51 mmol), HOBT (62.2 mg, 0.46 mmol), DMA (2 mL) and NMM (0.127 mL, 1.15 mmol). The reaction was stirred for 1 hour at room temperature and then diluted with EtOAc (0.2 mL) followed by H2O (4 mL). The resulting solids were washed in H2O and collected by filtration. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.11 (1H, d, J=1.9 Hz), 8.52 (1H, d, J=7.5 Hz), 8.28 (1H, dd, J=8.3, 2.3 Hz), 7.94-8.05 (1H, m), 7.90 (1H, dd, J=8.4, 1.5 Hz), 7.50-7.58 (1H, m), 3.72-3.89 (1H, m), 3.19 (2H, q, J=10.3 Hz), 2.95 (2H, d, J=11.9 Hz), 2.40-2.48 (2H, m) 1.82 (2H, d, J=13.1 Hz), 1.52-1.67 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[N:16]1.[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:23][CH:22]=2)=[N:16]1
Reactant: C#CC(C)(C)C
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)cc3)[nH]c2=O)c1
Yield: 27.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (Intermediate-98, 0.060 g, 0.120 mmol), 3,3-dimethylbut-1-yne (0.014 g, 0.181 mmol), TBAF (0.094 g, 0.362 mmol), bis(triphenylphosphine)palladium (II)chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.03 (s, 6H), 1.30 (s, 9H), 2.50 (m, 1H), 4.27 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 3H), 7.61 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.38 (m, 1H); MS (m/z): 449.9 (M−H)−.
Reaction SMILES: [Na].[F:2][C:3]([F:13])([F:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O-:5].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Br)[CH2:19][CH3:20])[CH3:15]>CN(C)C=O>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([F:12])([F:13])[F:2])[CH2:19][CH3:20])[CH3:15]
Reactant: [O-]C(c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)C(Br)CC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)OC(c1ccccc1)C(F)(F)F
Reaction time: 96 h

Procedure:
10.3 g of the sodium-2,2,2-trifluoro-1-phenylethanolate, obtained according to the process of Step A, are transferred into a three-neck flask with 50 ml dimethylformamide. After complete mixing, there is slowly added while cooling with an ice-bath a cooled mixture of 9.4 g ethyl-2-bromobutyrate and 35 ml dimethylformamide. The reaction is strongly exothermic and external cooling is applied so that the temperature of the reaction mixture does not go over 20°. The stirring and the cooling of the mixture are kept for four days.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[F:38][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1cccc(C(F)(F)F)c1)C1CC(F)CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81) (200 mg, 0.45 mmol) in DCM (20 ml) cooled at −20° C. was treated with DAST (0.148 ml, 1.11 mmol) and the mixture was first stirred 1 h at −20° C. then 18 hrs at RT. The reaction was quenched with NaHCO3 sat. sol. and the aqueous phase extracted with DCM (3×5 ml), dried over MgSO4 and evaporated. The residue was purified by Biotage SNAP-Si column (25 g) eluting with petroleum ether/EtOAc from 90/10 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D82) (110 mg)
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: Clc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3Cc4cccc(Cl)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 33.7 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 115 mg of 4-chloroisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 70 mg of the target compound.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:14]2[O:18][C:17](=[N:19][NH2:20])[C:16](=C=O)[CH2:15]2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[C:23](O)(=[O:25])C>CN(C)C=O>[OH:25][CH2:23][CH:15]1[C:14]([C:6]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)=[N:20][NH:19][C:17](=[O:18])[CH2:16]1
Reactant: CC(=O)O
Reactant: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2=NNC(=O)CC2CO)cc(OC)c1OC

Procedure:
7.0 g (0.222 mol) of the compound prepared in section (a) are stirred in 20 ml of dimethylformamide and 1 ml of acetic acid at 80° C. for 5 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride, the methylene chloride mixture is washed with potassium carbonate solution and concentrated and the residue is recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[F:29])[NH:25][N:24]=[CH:23]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][C:28]=2[F:29])[NH:25][N:24]=[CH:23]3)=[O:18])=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
The product of Example 4 Step 2 (240 mg, 0.903 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (137 mg, 0.903 mmol, 1.0 equiv), and EDC (207 mg, 1.084 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.151 mL, 1.084 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 83 mg (23%) of the title compound as an off white solid. MS (ES+) m/e 399 [M+H]+
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:50][CH:51]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[CH2:52][C:53]([O-])=[O:54])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Li+].Cl.CNC.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)C>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH:51]([NH:50][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:52][C:53]([N:2]([CH3:3])[CH3:1])=[O:54])=[CH:57][CH:58]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(=O)[O-])c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 375.2 %

Procedure:
HATU (152 mg, 0.40 mmol) was added in one portion to lithium 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 97) (200 mg, 0.36 mmol), dimethylamine hydrochloride (48.0 mg, 0.59 mmol) and N,N-diisopropylethylamine (0.190 mL, 1.09 mmol) in N-methyl-2-pyrrolidinone (3.0 mL) at room temperature under argon. The resulting solution was stirred overnight. Diethyl ether added to precipitate the crude product which formed as a gum. This was rinsed with Et2O and dried to give the crude gum (770 mg) which was used in subsequent reactions without further purification.