Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[C:4]([C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]1[C:16]([CH:17]=[CH:18][CH:19]=[C:20]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N+:15]2[O-])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OS([O-])(=O)=O.[Na+]>O>[C:4]([C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:15]2)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cccc2c1nc1ccc(C(=O)c3ccccc3)cc1[n+]2[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc2c1Nc1ccc(C(=O)c3ccccc3)cc1N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a boiled ethanol solution (300 mL) of 7-benzoyl-1-ethoxycarbonylphenazine 5-oxide (4.00 g, 10.7 mmol. obtained in Reference Example 1) was dropwise added for a period of one hour an aqueous solution (150 mL) of 85% sodium hydrosulfate (8.86 g, 43.2 mol.) in gaseous nitrogen atmosphere. After the dropwise addition was complete, the reaction mixture was further heated under reflux for 10 minutes. The refluxed mixture was then cooled to room temperature. To the cooled mixture was added water (150 mL). Thus deposited crystalline product was collected by filtration and washed with water. The washed product was placed under reduced pressure at 40° C. for 16 hours in the presence of diphosphorus pentoxide to dryness. Thus, 3.10 g (81%) of the desired compound was obtained as a brown-violet crystalline product. mp: 175-177° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH2:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[BH3-][C:18]#N.[Na+].C=O>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH:15][CH3:18])[C:6]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)c1cc(N)c(O)c(C(C)(C)C)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 14.8 %

Procedure:
A mixture of 2,4-di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol), NaBH3CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 mL) was stirred at reflux for 3 h. After removal of the solvent, the residue was purified by column chromatography (petroleum ether-EtOAc, 30:1) to give 2,4-di-tert-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 15%). 1HNMR (DMSO-d6) δ 8.67 (s, 1H), 6.84 (s, 1H), 5.99 (s, 1H), 4.36 (q, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 3H), 1.23 (s, 18H); ESI-MS 236.2 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](OC2C=CC=CC=2)=[N:27][C:28]#[N:29])=[CH:21][CH:20]=1>CN(C=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26](=[N:27][C:28]#[N:29])[O:25][C:22]4[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=4)=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A solution of Example 1E (0.4 g, 1.56 mmol) and diphenyl cyanocarbonimidate (0.372 g, 1.56 mmol) in DMF (10 mL) was heated to 90° C. for 2 days, cooled to room temperature, quenched with water, and filtered. The filter cake was suspended in ethanol and filtered. The filtrate was concentrated and purified by flash column chromatography on silica gel with 5 to 8% methanol/dichloromethane to provide the desired product (150 mg). MS(ESI(+)) m/e 401(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H); 8.27 (s, 1H); 7.67 (d, J=8.4 Hz, 2H); 7.50-7.43 (m, 4H); 7.36-7.29 (m, 3H); 2.29 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:42])[CH3:41]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([N:72]([C:13](=[O:15])/[CH:12]=[CH:11]/[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (277 mg, 1.14 mmol) and 1-hydroxy-7-azabenzotriazole (155 mg, 1.14 mmol) were dissolved in dichloromethane (3 mL) and N,N-dimethylformamide (3 mL). The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (254 mg, 1.32 mmol) was added. The solution for stirred for 10 min at 0° C., before a solution of 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate in dichloromethane (3 mL) was added. The solution was stirred for 18 hours, while it was warming up slowly to room temperature. It was diluted with ethyl acetate (100 mL) and extracted with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatogrpahy on silica (45 g) with ethyl acetate/heptane (2:1) to give 427 mg of 3-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: ClC1C=CC(C(OO)=[O:9])=CC=1.[CH3:12][S:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:19]=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:25])([F:24])[F:26])[N:22]=2)[N:19]=1)=[O:9]
Reactant: O=C(OO)c1ccc(Cl)cc1
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(SC)nn23)C1
Solvent: ClC(Cl)Cl
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(S(C)=O)nn23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
4-chloroperbenzoic acid (36 mg, 0.134 mmol, 1 eq) is added to a solution of 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 33 (50 mg, 0.134 mmol) in chloroform (2 ml) at −30° C. After 30 minutes, the mixture is warmed to room temperature then stirred for additional 16 hours. After hydrolysis with a saturated aqueous NaHCO3 solution (2 ml) and extraction with CHCl3 (2 ml), the cumulated organic layers are dried over MgSO4 and condensed under reduced pressure. The resulting crude product is purified by reverse phase liquid chromatography (gradient acetonitrile/water/TFA) to yield 1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][N:19]([C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: COc1cccc(N=C=O)c1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2cccc(OC)c2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 3-methoxy phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford a racemate as a colourless liquid (230 mg, 80%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1.ClCCl>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:16])[CH3:11]
Reactant: Cc1ccc(F)c(O)c1
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cc(C)ccc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 2-fluoro-5-methyl-phenol (0.97 mL, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 4 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded 3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.12 g, 52%) as a clear oil: HR-ES-MS m/z calculated for C13H15O3F [M+H]+ 239.1078, observed 239.1078; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.0 Hz, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.69 (s, 1H), 7.01-7.19 (m, 2H), 7.30 (dd, J=10.7, 8.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[OH:15])#[N:4].IC.[CH3:18]COC(C)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:18])#[N:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Reaction time: 2 h

Procedure:
Sodium hydride (9 g, 0.24 mol as 60% wt. disp. mineral oil) was added to a solution of the phenol from Step C (36.1 g, 204 mmol) in 400 mL of dry DMF at room temperature. Iodomethane was added (14 mL. 0.22 mol) was added, and the reaction was stirred for 2 hours. The mixture was poured into EtOAc/water, and the organic layer was washed with water and brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the titled.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[OH-:14].[Na+].Cl>>[ClH:1].[Cl:1][C:2]1[NH:3][C:4](=[O:14])[C:5]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: Cc1ccnc2nc(Cl)nc(Cl)c12
Agent: Cl
Agent: [Na+]
Product: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Reaction time: 1 h

Procedure:
2,4-Dichloro-5-methyl-pyrido[2,3-d]pyrimidine (302 mg, 1.4 mmol) was suspended at ambient temperature in aqueous 1N NaOH solution (6 ml) and stirred for 1 h. The pH was adjusted to 7 with aqueous 25% HCl solution and the mixture was washed two times with dichloromethane. The aqueous layer was brought to dryness under reduced pressure to give 344 mg (1.48 mmol; quant.) 2-chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride as off-white solid which was used in the next step without further purification. MS: m/e=195.9 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1.[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)c(OC2CCCCO2)c1

Procedure:
To solution of 4-bromo-3-hydroxybenzoic acid (available from Combi-Blocks Inc.) (2.50 g, 11.5 mmol) in DCM (100 mL) at 23° C., was added 3,4-dihydro-2H-pyran (available from Aldrich) (2.10 mL, 23.0 mmol) followed by PPTS (0.289 g, 1.15 mmol). The reaction gave a mixture of bis THP protected compound and 26.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].[I-].[K+]>CC(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC(C)=O)cc1
Yield: 188.2 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (30.4 g), chloroacetone (8.5 g) potassium carbonate (54 g) and potassium iodide (33.3 g) was refluxed in acetone for 4 hours. The reaction mixture was cooled, the solids filtered and the solvent evaporated. The residue was partitioned between water and ether, the layers separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound (36 g). τ (CDCl3) 7.75 (3H, s), 6.11 (3H, s) 5.39 (2H, s), 3.09 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[CH:23])[CH:17]=1)#[CH:15]>>[C:14]([C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: C#Cc1cccc(C#C)c1
Reactant: COC(=O)CCc1ccc(I)cc1
Product: C#Cc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (120 mg, 0.41 mmol) and 1,3-diethynylbenzene (0.06 mL, 0.45 mmol) according to the general procedure IC, with the exception that the reaction was performed at room temperature, to give 52 mg (43%) of an yellow-brown gummy oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.41 (EtOAc:hexanes, 1:2); 1HNMR (CDCl3) δ 7.65 (s, 1H), 7.49-7.42 (m, 4H), 6.31-7.29 (m, 1H), 7.19-7.17 (m, 2H), 3.67 (s, 3H), 3.09 (s, 1H), 2.99-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.1, 135.0, 131.8, 131.7, 128.4, 123.7, 122.4, 120.8, 90.0, 88.0, 82.8, 77.7, 51.6, 35.3, 30.8; EI-MS m/z 288 (M+).
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O>[CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccn(C(C)C)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1ccc(C(=O)O)cc1=O
Temperature: 50 °C

Procedure:
To methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (225 mg) was added NaOH (550 μL of 25% w/w, 4.3 mmol) and water (0.6 mL). The mixture was rapidly stirred and heated at 50° C. for 1 h. The mixture was cooled, acidified to pH 2 with 6N aq. HCl and the solids collected, rinsing with water and ACN (2×). The solid was dried in vacuo to give 1-isopropyl-2-oxo-pyridine-4-carboxylic acid as a white solid. ESI-MS m/z calc 181.2, found 182.3 (M−1)−. Retention time: 0.86 minutes (3 min run).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)=[CH:5][N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1.[NH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23].CCCCCC.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[N:8]=2)=[CH:5][N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: C[C@H](O)CN
Reactant: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(I)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Yield: 96.8 %

Procedure:
A mixture of 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine B-1-2 (16 g, 40 mmol) and (s)-1-amino-propan-2-ol (9 g, 122 mmol) in THF (160 mL) was heated to reflux overnight. TLC (hexane: EtOAc=2:1) showed the reaction was complete, EtOAc (80 mL) and saturated aqueous NaCl (80 mL) were added to the mixture, and the layers were separated. The organic layer was separated, washed with saturated aqueous NaCl (30 mL), dried over Na2SO4 and concentrated to give (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (15 g, 96.9%) as a brown oil.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:20][N:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:20][N:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CN(C)C)c1ccc(OC)cc1
Yield: 20.9 %

Procedure:
A gentle nitrogen flow was applied to a 100 ml balloon flask provided with magnetic stirring and 0.455 g (0.0120 mol) of sodium borohydride was mixed with 10 ml of ethanol. Thereafter, 1 g (0.0040 mol) of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate was added. The mixture was stirred for 24 hours at room temperature and then 3 ml of water were added. The ethanol was removed in the rotary evaporator and 20 ml of water and 20 ml of dichloromethane were added over the residue. The mixture was stirred and the phases were separated. The process continued with the organic phase. 20 ml of water were added, the mixture was acidified to acid pH and decanted. The aqueous phase was washed with 20 ml of dichloromethane and was then basified to basic pH. The product was extracted from the aqueous phase with 20 ml of dichloromethane. It was dried with sodium sulfate, was filtered and the solvent was removed under vacuum to give 0.21 g of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)propionate (Yield: 21%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[C:9](C#N)=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH:35]([N:38](CC)C(C)C)(C)C.[C:44](Cl)(=[O:46])[CH3:45]>C1COCC1.ClCCl>[C:44]([N:14]1[CH2:13][CH2:12][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]=4[C:35]#[N:38])[CH:9]=2)[CH2:16][CH2:15]1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1c(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn2c1C1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4c(C#N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 4-amino-5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (50 mg, 0.11 mmol) in THF (2 mL) was added. N,N-diisopropylethylamine (39 μL, 0.22 mmol) followed by acetyl chloride (8.8 μL, 0.11 mmol). The mixture was stirred at rt overnight. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (20 mL), brine, and was dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography to obtain the desired product (20 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.02 (s, 1H), 7.86 (d, 1H), 7.68 (s, 1H), 7.40-7.24 (m, 5H), 7.11 (d, 1H), 5.66 (s, 2H), 4.60-4.56 (m, 1H), 3.00-3.96 (m, 1H), 3.71-3.62 (m, 1H), 3.22-3.18 (m, 1H), 2.66-2.61 (m, 1H), 2.02 (s, 3H), 2.04-1.88 (m, 4H); LC-MS m/z[M+H]+491.3, RT 2.83 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([Cl:21])C(I)=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.[C:33](=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([Cl:21])[C:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([CH3:33])[CH:25]=3)=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(B(O)O)c1
Reactant: CCOP(=O)(CSc1nc2cc(I)c(Cl)cc2[nH]1)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOP(=O)(CSc1nc2cc(-c3ccc(Cl)c(C)c3)c(Cl)cc2[nH]1)OCC
Temperature: 130 °C

Procedure:
To a solution of (6-Chloro-5-iodo-1H-benzoimidazol-2-ylsulfanylmethyl)-phosphonic acid diethyl ester (Intermediate 1, 255 mg, 0.55 mmol) in toluene (2 mL) was added 4-chloro-m-tolueneboronic acid (185 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol), and potassium carbonate (305 mg, 2.2 mmol) as a solution in H2O (1 mL). The resulting mixture was heated in a sealed microwave vial at 130° C. for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride, partitioned between CH2Cl2 and H2O, and filtered through a Celite™ pad. The organic and aqueous layers were separated. The organic layer was dried with MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by flash chromatography (SiO2, 12 g) using a gradient up to 9:1 EtOAc:Hexane to isolate the title compound 12-1.
Reaction SMILES: [Cl:1][C:2]([F:19])([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)[OH:4].[O:20]=[C:21](N1C2C(=CC(CO)=CC=2)CC1)[CH2:22][C:23](=O)[CH3:24]>S(=O)(=O)(O)O>[Cl:1][C:2]([F:18])([F:19])[C:3]([C:5]1[CH:13]=[C:12]2[C:11]3=[C:7]([CH2:8][CH2:9][N:10]3[C:21](=[O:20])[CH:22]=[C:23]2[CH3:24])[CH:6]=1)([OH:4])[C:14]([F:17])([F:15])[F:16]
Reactant: CC(=O)CC(=O)N1CCc2cc(CO)ccc21
Reactant: OC(c1ccc2c(c1)CCN2)(C(F)(F)F)C(F)(F)Cl
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)Cl)cc13)CC2

Procedure:
By the method of Example 7, α-(chlorodifluoromethyl)-α-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol is converted to α-(chlorodifluoromethyl)-α-trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 160°-164°, which is cyclized by heating in sulfuric acid to give 1,2-dihydro-8 [2-chloro-2,2-difluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,-2,1-ij]quinolin-4-one, m.p. 294°-295°.